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Sample records for justin yifu lin

  1. China’s Internal Migration, Public Policies, and Economic Growth

    Science.gov (United States)

    2012-12-01

    the 40 Ibid. 41 Justin Yifu Lin, The China Miracle (Hong Kong: The Chinese University of Hong Kong...Chinese Economy Transitions and Growth, 69. 77 Dorothy J. Solinger, Contesting Citizenship in Urban, 41. 78 Justin Yifu Lin, The China Miracle, 69...76 Liang, Zai, and Michael J. White. “Internal Migration in China, 1950–1988.” Demography 33, no. 3 (August 1996): 375–384. Lin, Justin

  2. Traditional Confucianism in modern China:Ma Yifu's ethical thought

    Institute of Scientific and Technical Information of China (English)

    Chai Wenhua

    2006-01-01

    Modern neo-Confucianism is studied at two levels,one is at the historical level and the other at the academic level.Modern neo-Confucianism at the historical level was developed in the modern context,but its basic content belongs to the traditional Confucianism or the study of Confucian classics.Modern neo-Confucianism at the academic level recognizes both the deficiencies of the traditional Confucianism and rationality of western learning,and dedicates itself to the modernization of Confucianism.Though Ma Yifu's moral philosophy is developed in the context of modern Chinese culture,it fails to deal with the problem of modern transformation of Confucian ethical values and its content still belongs to the traditional Confucianism.So it should be labeled as the modern neo-Confucianism in the historical sense.In this Paper,the author makes a systematic exploration and an evaluation of Ma Yifu's ethical thought.

  3. Justine user`s manual

    Energy Technology Data Exchange (ETDEWEB)

    Lee, S.R.

    1995-10-01

    Justine is the graphical user interface to the Los Alamos Radiation Modeling Interactive Environment (LARAMIE). It provides LARAMIE customers with a powerful, robust, easy-to-use, WYSIWYG interface that facilitates geometry construction and problem specification. It is assumed that the reader is familiar with LARAMIE, and the transport codes available, i.e., MCNPTM and DANTSYSTM. No attempt is made in this manual to describe these codes in detail. Information about LARAMIE, DANTSYS, and MCNP are available elsewhere. It i also assumed that the reader is familiar with the Unix operating system and with Motif widgets and their look and feel. However, a brief description of Motif and how one interacts with it can be found in Appendix A.

  4. "Justine's story" and the art of nursing.

    Science.gov (United States)

    Baker, Paige

    2008-03-01

    The author of this response to Dr. Kathryn Gramling's research on the art of nursing as perceived by patients agrees with patient Justine's assessment of the art. The author believes that the expression of a nurse's personality during the caring process creates the art. Justine saw all her nurses, even the brusque one, as performing in a caring way, each according to his/her own personality. The author believes this definition of the art of nursing is valid.

  5. Kroonika esitleb : Justin Timberlake ja Rod Stewart / Justin Timberlake ; interv. Katrin Lust-Buchanan

    Index Scriptorium Estoniae

    Timberlake, Justin

    2006-01-01

    Meesteajakirja GQ auhindade jagamise tseremoonial Londonis sai ajakirja Kroonika reporter jutule aasta rahvusvahelisima mehe tiitli pälvinud Justin Timberlake'i ja elutööpreemia saanud Rod Stewartiga

  6. Kroonika esitleb : Justin Timberlake ja Rod Stewart / Justin Timberlake ; interv. Katrin Lust-Buchanan

    Index Scriptorium Estoniae

    Timberlake, Justin

    2006-01-01

    Meesteajakirja GQ auhindade jagamise tseremoonial Londonis sai ajakirja Kroonika reporter jutule aasta rahvusvahelisima mehe tiitli pälvinud Justin Timberlake'i ja elutööpreemia saanud Rod Stewartiga

  7. Justin Bieber - en toneangivende formidler til tweens

    OpenAIRE

    Lundeby, Maria Celine Kolberg

    2014-01-01

    Ønsket mitt med oppgaven har vært å skape en bevissthet om at populærkulturen er en formidler av noe, og at dette noe bærer i seg potensialet til å ha direkte betydning for vanlige menneskers liv. Gjennom dette utblikket har målet vært å synliggjøre noen eksempler på hvordan det som formidles kan bli gode innfallsvinkler til samtaler om og forkynnelse av kristen tro til tweens. Selv om denne oppgaven har tatt utgangspunkt i et veldig konkret eksempel, Justin Bieber, er de grunnleg...

  8. Justin Bieber欧美新偶像

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    来自加拿大年仅16岁的青少年偶像贾斯汀·比伯Justin Bleber凭借个人第二张专辑《我的世界2.0》(My World2.0)以绝对优势统治了美国专辑榜。更值得一提的是,这位年轻歌手发表这张专辑仅仅才一周。

  9. PEOPLE & POINTS

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Three days before the Chinese lunar New Year,Justin Yifu Lin,the founder and Director of the China Center for Economic Research at Peking University,was named by the World Bank as its chief economist and senior vice president for devel-

  10. Meet EPA Researcher Justin Conley, Ph.D.

    Science.gov (United States)

    Justin Conley is a postdoctoral researcher investigating the toxicity of endocrine disrupting chemicals and new approaches for water quality monitoring. When he is not in the lab, he is busy brewing beer and exploring the outdoors.

  11. What’s Driving China’s Transition?

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    "Development and Transition:Idea,Strategy and Viability"is the title of a lecture given by Justin Yifu Lin,professor at the China Center for Economic Research of Peking University, when he spoke at the Cambridge University-sponsored Marshall Lectures from October 31-November 1.In his talk, Lin elaborated on the successes and failures of China’s econom- ic transition along with those of other developing countries. Excerpts follow:

  12. Sugar Free with Justin T.: Diabetes Education through Community Partnerships

    Science.gov (United States)

    Thomas, Justin B.; Donaldson, Joseph L.

    2014-01-01

    This article describes the design, development, and delivery of an Extension community cable television program, "Sugar Free with Justin T.," in Roane County, Tennessee. The program targets diabetics, pre-diabetics, and those who care for them, with practical information and demonstrations to improve dietary quality. In addition to…

  13. Sugar Free with Justin T.: Diabetes Education through Community Partnerships

    Science.gov (United States)

    Thomas, Justin B.; Donaldson, Joseph L.

    2014-01-01

    This article describes the design, development, and delivery of an Extension community cable television program, "Sugar Free with Justin T.," in Roane County, Tennessee. The program targets diabetics, pre-diabetics, and those who care for them, with practical information and demonstrations to improve dietary quality. In addition to…

  14. 喜读林毅夫新思维——“追赶式”发展策略之“优”

    Institute of Scientific and Technical Information of China (English)

    郭益耀

    2009-01-01

    最近友人传来了一篇颇令人惊奇与欣奋的、刚由世界银行发表不久的论文:Justin Yifu Lin and Zhiyun Li, "Endogenous Institution Formation under a Catching-up Strategy in Developing Countries", Policy Research Working Paper, WPS 4794, Development Economics Vice Presidency, The World Bank, December 2008.

  15. Practical Look at the CPC Blueprint

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The Economic Observer and Nanfang Weekend respectively conducted interviews with Pan Yue,Vice Minister of the State Environmental Protection Administration,and Professor Justin Yifu Lin,Director of the China Center for Economic Research,Peking University,on how they view comments made in General Secretary of the Communist Party of China)CPC)Hu Jintao’s report at the 17th National Congress of the Party.Interviews are reproduced here.

  16. How is Sense of Place Possible? An Analysis of Yi-Fu Tuan’s Space and Place

    Institute of Scientific and Technical Information of China (English)

    Wang Jian; Li Ziqing; Sun Hui; Yang Zi

    2016-01-01

    In the first century of Anthropology (1870-1970), almost all social sciences studies focused on“objective”,“rational”,“collective”, and “universal” socio-cultural facts. This orien-tation excluded and marginalized those “subjec-tive”,“individual” and “non-rational” fields in the discourse system of the discipline. “Sense”was such a field, refused by the gatekeepers of tra-ditional anthropology. Since 1980s, more and more anthropologists have paid attention to the study of sense. laying the foundations for an “anthropology of the sen-ses”. With the gradual influence of Western An-thropology of the senses, “sense of place” is be-coming a current academic phrase in Chinese An-thropology. Meanwhile, a fundamental question has to be asked:how is sense of place possible? In order to explore this question, we must go back to Yi-Fu Tuan, a renowned humanistic geographer and his master work, Space and Place. Space and Place contains a total of fourteen chapters and can be divided into three parts. The first part, chapters 1 to 3, discusses three key words:experience, space, and place. Meanwhile, this part identifies the fundamental question of the book:how do human beings understand and expe-rience the world? The second part, ranging from chapters 4 to 9 , and introduces the relationship be-tween sense and space. The third part,chapters 10 to 14 , interprets the relationship between place and sense. Although the latter two parts introduce the relationship between the “Sense and Space”and “Place and Sense”, the interrelation of space-sense-place runs through the whole book. The three key words ( experience, space and place ) are fully reflected in the title of the book ( Space and Place—the Perspective of Experience. What, then, is the nature of experience? Tuan holds that the essentiality of experience is how a person knows and constructs reality, ran-ging from inchoate feelings to explicit conceptions. Essentially

  17. TWO VIEWS ON F. DOSTOEVSKY: OSCAR VON SCHOULTZ AND THE REVEREND JUSTIN (POPOVITCH

    Directory of Open Access Journals (Sweden)

    Velikoselskiy A. V.

    2011-11-01

    Full Text Available This article provides a comparative analysis of two studies by two researchers of Dostoevsky’s creative work — Finnish slavist Oscar von Schoultz and Serbian religious thinker The Reverend Justin Popović. It focuses primarily on the system and evolution of positive and negative characters of Dostoevsky's novels in the context of faith and unbelief.

  18. Abject Magic: Reasoning Madness in Justine Larbalestier's "Magic or Madness" Trilogy

    Science.gov (United States)

    Potter, Troy

    2013-01-01

    This paper explores the representation of magic and madness in Justine Larbalestier's "Magic or Madness" trilogy (2005-2007). Throughout the series, magic is constructed as an abject and disabling force that threatens to disable magic-wielders, either through madness or death. Despite being represented as a ubiquitous force, the…

  19. LIN Qiu-cheng (

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Professor LIN Qiu-cheng, born in Xianyou county, Fujian Province in March 1931, was graduated from Fujian Medical College in 1954 and assigned to Union Hospital affiliated to Fujian Medical College. From 1958 to 1961, he studied traditional Chinese medicine (TCM) systematically and was awarded the third class prize by State Health Ministry for his excellent score. After then, he assumed office as vice president of Fujian Research Institute of TCM. Also he had been the vice president of Fujian People's Hospital and Fujian Second People's Hospital. Now, Prof. LIN is chief physician of Fujian Research Institute of TCM, tutor of postgraduates on integrated traditional Chinese and western medicine (TCM-WM) of Fujian College of TCM, supervisor of Ph.D. students in Beijing University of TCM, evaluation expert of State Drug Administration, member of State Drug Committee of Clinical Research Base, director of Committee on Medical Ethics and director of Research Department on Gerontology of Fujian Research Institute of TCM.……

  20. Justin Bieber, do doc ao Instagram: a estetização da vida

    Directory of Open Access Journals (Sweden)

    Denise Tavares

    2013-12-01

    Full Text Available Alguns documentários biográficos de celebridades reafirmam um modelo de produção audiovisual que encerra a história de vida no show e na fama, articulando o tensionamento entre biografia, tecnologia, experiência estética e afeto. Tais imbricamentos são ainda mais visíveis quando considerada a fruição desta celebridade, “consumida” em outras possibilidades biográficas que remixa webvideos postados no Youtube e/ou fotos no Instagram. Para discutir estas questões, o artigo destaca Justin Bieber, tendo como ponto de partida o documentário Justin Bieber – Never Say Never (2011, de Jon M. Chu e o Instagram, em um recorte que privilegia a experiência dos desejos dos fãs.

  1. Justin Bieber 为新单曲拍MV现场跳贴身热舞

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    当地时间2012年4月21日,小天王贾斯汀一比伯(Justin Bieber)在美国洛杉矶为新曲《男朋友》拍摄MV,当天拍摄的是与女主角的亲密戏码,小天王频频笑场NG。

  2. [Research progress of Lin28 function].

    Science.gov (United States)

    Shen, Honghong; Niu, Yun

    2014-09-01

    As a highly conserved RNA binding protein, Lin28 is a specific post-transcriptional inhibitor of let-7 biogenesis and can inhibit the let-7 processing and synthesis. Lin28 is involved in the stem cell proliferation and promote the rapid growth of embryonic stem cells. Lin28 plays an important role in the formation of tumor stem cells. Overexpression of Lin28 promotes the tumor cell proliferation and is associated with advanced human cancers. Lin28 can promote tissue repair.

  3. Justin Bieber, do doc ao Instagram: a estetização da vida

    OpenAIRE

    Denise Tavares; Raphael Pinto

    2013-01-01

    Alguns documentários biográficos de celebridades reafirmam um modelo de produção audiovisual que encerra a história de vida no show e na fama, articulando o tensionamento entre biografia, tecnologia, experiência estética e afeto. Tais imbricamentos são ainda mais visíveis quando considerada a fruição desta celebridade, “consumida” em outras possibilidades biográficas que remixa webvideos postados no Youtube e/ou fotos no Instagram. Para discutir estas questões, o artigo destaca Justin Bieber,...

  4. LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells.

    Science.gov (United States)

    Zhou, Jianbiao; Ng, Siok-Bian; Chng, Wee-Joo

    2013-05-01

    LIN28 (LIN28A) is a reprogramming factor and conserved RNA-binding protein. LIN28B is the only homolog of LIN28 in humans, sharing structure and certain function. LIN28/LIN28B has been identified to be overexpressed in a wide range of solid tumors and hematological malignancies. Blockage of let-7 miRNA biogensis and subsequent derepression of let-7 miRNA target genes by LIN28/LIN28B play important roles in cancer progression and metastasis. We will first provide an overview of LIN28/LIN28B gene and protein structures, followed by summary of the studies that showed their aberrant expression in primary human cancers and relevant clinical significance with emphasis on their roles in formation of cancer stem cells. Next, we will highlight the current knowledge of LIN28/LIN28B regulators and molecular mechanisms of LIN28/LIN28B-mediated oncogenesis. The potential medical applications for targeting LIN28/LIN28B will also be discussed in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Justin Bieber

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    贾斯汀·比伯是人气正在迅速上升的加.拿大少年歌手。他的个人单曲《OneTime》一经推出便风靡全球,第二首单曲《OneLessLonelyGirl》首周上榜便取得了榜单第16位的好成绩。尤其是(Baby))这首歌曲在You.Tube上的点击量超过四亿。那么年纪轻轻的贾斯汀·比伯是怎么走上音乐之路的呢?

  6. 林毅夫胆识睿智成大器夫妻恩爱比翼飞%Yifu Lin:Courage and Wisdom Leads to Success;Happy Marriage Ensures Each Other's Progress

    Institute of Scientific and Technical Information of China (English)

    丁跃忠

    2008-01-01

    @@ 在世界经济学界,林毅夫无疑是一位传奇人物,这位现任北京大学教授、中国经济研究中心主任的台湾籍经济学家刚刚被任命为世界银行副行长.他的人生经历充满传奇,事业如是,姻缘亦如是.

  7. The Lin28 Expression in Stallion Testes.

    Science.gov (United States)

    Lee, Geumhui; Jung, Heejun; Yoon, Minjung

    2016-01-01

    The molecular markers for specific germ cell stages can be utilized for identifying, monitoring, and separating a particular stage of germ cells. The RNA-binding protein Lin28 is expressed in gonocytes of human fetal testes. The Lin28 expression is restricted to a very small population of spermatogonial cells in human, mice, and monkey. The main objective of this study was to investigate the expression pattern of Lin28 in stallion testes at different reproductive stages. Based on the presence or absence of full spermatogenesis and lumina in seminiferous tubules, the testicular samples were categorized into two reproductive stages pre-pubertal and post-pubertal. We performed a reverse transcription polymerase chain reaction to confirm the presence of Lin28 mRNA in the testicular tissues and a western blot analysis to verify the cross-reactivity of rabbit Lin28 antibody with horse testicular tissue. For immunohistochemistry, Lin28 (rabbit anti-human), GATA4 (goat anti-human) or DAZL (goat anti-human) antibodies were used. The results of RT-PCR confirmed the expression of Lin28 mRNA in the stallion testes. The western blot analysis showed that the expression of 28 kDa Lin28 protein was localized in the cytoplasm of spermatogonia at both reproductive stages. The numbers of Lin28-positive germ cells per 1000 Sertoli cells in pre- and post-pubertal stages were 253 ± 8.66 and 29.67 ± 2.18, respectively. At both reproductive stages, all Lin28 positive cells showed no co-stained with GATA4 antibody, whereas only some of the Lin28-positive germ cells showed co-staining with DAZL antibody. The results from whole-mount staining showed that the Lin28 expression was limited to Asingle (As) and Apaired (Apr) spermatogonia. In conclusion, Lin28 might be utilized as a molecular marker for undifferentiated spermatogonial stem cells when used with DAZL antibody.

  8. The Victorian Philanthropic Quixote: Donna Quixote, by Justin McCarthy

    Directory of Open Access Journals (Sweden)

    Pedro Javier Pardo

    2012-12-01

    Full Text Available The paper undertakes the analysis of a little known Victorian quixotic novel, Donna Quixote, by Justin McCarthy. In so doing, it places the latter, in the first place, within the conception of quixotism characteristic of the Victorian age and, in the second place, within the previous tradition of female quixotes, particularly as a response to George Eliot’s Middlemarch. Then, the text studies the novel’s originality within the English quixotic tradition, which lies in the way it relates quixotism to both philanthropy and feminism, not just by means of the heroine but also of some quixotic secondary figures, and argues the author’s conservative position in the debate on women’s rights known as the woman question. Finally, the paper illustrates such a position and its ideological context by presenting another “Donna Quixote,” in this case a satiric cartoon on the so-called new woman.

  9. LINS Curve in Romanian Economy

    Directory of Open Access Journals (Sweden)

    Emilian Dobrescu

    2016-02-01

    Full Text Available The paper presents theoretical considerations and empirical evidence to test the validity of the Laffer in Narrower Sense (LINS curve as a parabola with a maximum. Attention is focused on the so-called legal-effective tax gap (letg. The econometric application is based on statistical data (1990-2013 for Romania as an emerging European economy. Three cointegrating regressions (fully modified least squares, canonical cointegrating regression and dynamic least squares and three algorithms, which are based on instrumental variables (two-stage least squares, generalized method of moments, and limited information maximum likelihood, are involved.

  10. 以原创性的研究追求原创性的发现--读林毅夫《再论制度、技术与中国农业发展》%Seeking for Original Discovery by Original Research--Reading Justin Yifu's "On Institution, Technology and China's Agricultural Development Once More"

    Institute of Scientific and Technical Information of China (English)

    平新乔

    2001-01-01

    @@ 本人是由衷地钦佩那些为理论而理论、为学术而学术、为艺术而艺术的大师的.自然界、人类社会发展的内在逻辑能被某项研究清晰而简单地揭示出来,其意义是难以用"用"这个字涵盖的.将造化的秘密以公式、符号或数据完美地展示出来,这本身便是其乐无穷的.研究有纯理论研究与实证研究之分,实证研究照样可以是原创的.也许,一个超凡脱俗的人从当代经济学主流的角度出发会认为中国的经济体制的转型与演化只是"一小步",如同从飞机上看到的长江三峡只是一条小水沟,可以放浪形骸,大声妄言:为什么中国20年还走不完这一小步?但越来越多的人,其中也不乏象E.Maskin,L.Laffont与J.Tirole这样的理论大师,已注意到,一国从何处开始及如何进行改革是一个有意义的问题.林毅夫的新作《再论制度、技术与中国农业发展》(北京大学出版社,2000年版)中所收录的十来篇论文,对于这一问题的独立研究,有致用的政策意义,也有学术认识上的价值.

  11. The first federal budget under Prime Minister Justin Trudeau: Addressing social determinants of health?

    Science.gov (United States)

    Ruckert, Arne; Labonté, Ronald

    2016-08-15

    A challenging budget environment during the Harper years has meant that crucial investments in the social determinants of health (SDHs) have increasingly been neglected. The tabling of what is widely considered a more progressive budget with expansionary fiscal elements under the new Prime Minister, Justin Trudeau, raises the question as to what extent this budget invests in policy areas that are crucial for achieving a more equitable distribution in the social determinants of health, as promised in the Liberal party platform. In this commentary, we argue that the first Liberal budget represents a step in the right direction, but that this first step needs to be followed up with a sustained commitment to address the pervasive (and unfair) social inequalities that are the root cause of persistent health inequities in Canada. We conclude that the first Trudeau budget, while moving in the right direction, does not fully embody the sustained policy changes needed to effectively address SDHs, including a more expansive role for the federal government in the redistribution of income and wealth.

  12. "Bieber Fever". Um aðdáun unglingsstúlkna á Justin Bieber

    OpenAIRE

    Sigurlín Sumarliðadóttir 1989

    2013-01-01

    Í þessari ritgerð ætla ég að skoða hvort aðdáun unglingsstúlkna á poppstirninu Justin Bieber geti flokkast sem átrúnaður. Meginspurning ritgerðarinnar er: Getur aðdáun þessara stúlkna flokkast sem trú? Markmið ritgerðarinnar er að varpa ljósi á aðdáun þessarra stúlkna og og hvernig hún geti flokkast sem trú. Trú er stórt og áhugavert fyrirbæri sem hefur marga fleti. Trú er mis mikilvæg fyrir fólk og fyrir suma hefur hún ekkert vægi. Trú er svo margslungin að kannski má segja að...

  13. Different expression patterns of Lin28 and Lin28b in mouse molar development.

    Science.gov (United States)

    Dong, Ning; Liu, Yan; Zhang, Tiantian; Zhao, Lin; Tian, Jiangang; Ruan, Jianping

    2017-10-01

    The RNA-binding proteins Lin28 and Lin28b are expressed in many developing tissues and are involved in the biosynthesis of the microRNA let-7 family and embryogenesis processes. However, their roles in mammalian tooth development remain ill-defined. The spatiotemporal expressions of Lin28 and Lin28b during mouse molar odontogenesis from day E11.5 to P21 were examined through immunohistochemistry and western blot analysis. Both Lin28 and Lin28b were initially expressed in dental epithelium, but the expression patterns varied thereafter. Lin28 was expressed in tooth germ from early embryonic stages and was consistently expressed in the ameloblasts and odontoblasts throughout all stages of tooth development. However, positive staining of Lin28b gradually faded out with tooth germ development, before finally disappearing in tooth organ cells after birth. These results indicate that Lin28 was spatiotemporally expressed in tooth germ throughout tooth development progression and may play an active role in ameloblast and odontoblast differentiation, as well as matrix secretion and the mineralization of enamel and dentin. Its paralogue Lin28b may have a distinct function in tooth germ formation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. LIN-44/Wnt directs dendrite outgrowth through LIN-17/Frizzled in C. elegans Neurons.

    Directory of Open Access Journals (Sweden)

    Leonie Kirszenblat

    2011-09-01

    Full Text Available Nervous system function requires proper development of two functional and morphological domains of neurons, axons and dendrites. Although both these domains are equally important for signal transmission, our understanding of dendrite development remains relatively poor. Here, we show that in C. elegans the Wnt ligand, LIN-44, and its Frizzled receptor, LIN-17, regulate dendrite development of the PQR oxygen sensory neuron. In lin-44 and lin-17 mutants, PQR dendrites fail to form, display stunted growth, or are misrouted. Manipulation of temporal and spatial expression of LIN-44, combined with cell-ablation experiments, indicates that this molecule is patterned during embryogenesis and acts as an attractive cue to define the site from which the dendrite emerges. Genetic interaction between lin-44 and lin-17 suggests that the LIN-44 signal is transmitted through the LIN-17 receptor, which acts cell autonomously in PQR. Furthermore, we provide evidence that LIN-17 interacts with another Wnt molecule, EGL-20, and functions in parallel to MIG-1/Frizzled in this process. Taken together, our results reveal a crucial role for Wnt and Frizzled molecules in regulating dendrite development in vivo.

  15. [Effects of Lin28a and Lin28b on let-7 family activity].

    Science.gov (United States)

    Liu, Xue-Rong; Tian, Wen-Hong; Dong, Xiao-Yan; Wu, Xiao-Zhe; Lv, Jian-Xin; Wu, Xiao-Bing

    2011-11-01

    In this report, we study the effects of over-expression of Lin28a and Lin28b on let-7 family activity in HeLaS3. Firstly, we constructed pAAV2neo-Lin28a and pAAV2neo-Lin28b to express Lin28a and Lin28b, respectively. Then, pAAV2neo-Lin28a and pAAV2neo-Lin28b were transfected into HeLaS3, selected with G418 and obtained cell lines, HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b, to express Lin28a and Lin28b stably. Thereafter, we constructed eight plasmid vectors for detection of let-7 family activity based on pAAV2neo-Gluc-(Fluc). These vectors were further packaged into recombinant adeno-associated viral vectors (rAAV) which were used as sensors, nominated as Asensors, to detect inhibition activity of miRNA at post-transcriptional level. Subsequently, with HeLaS3 as a control, we assayed expression levels of Lin28a and Lin28b by Western blot, detected expression levels of let-7 family by QRT-PCR, and tested let-7 family activity by Asensors in HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b. Results demonstrated that both HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b could express Lin28a and Lin28b effectively. Compared with HeLaS3, the expression level of let-7 family except let-7e declined in HeLaS3/pAAV2neo-Lin28a. But declining extent among members of let-7 family was different. The let-7 family activity also decreased while the decreasing extent varied among members. Furthermore, the activity level was not consistent with its expression level for the same member in let-7 family. Compared with HeLaS3, both expression level and activity level of let-7 family in HeLaS3/ pAAV2neo-Lin28b were decreased. However, the decreasing extent of let-7 family expression changes was larger than that of HeLaS3/pAAV2neo-Lin28a while the decreasing extent of activity changes was similar. In this study, we established a method to detect and compare post-transcriptional inhibition level mediated by miRNA complementary targets. We firstly clarified the effect of Lin28a

  16. Man – body and soul, as well as the relationship between them in the view of St. Justin the Martyr and Philosopher

    Directory of Open Access Journals (Sweden)

    ROTARU Ioan-Gheorghe

    2014-11-01

    Full Text Available Among the first Church Fathers, where we find the concern for anthropological issues, is St. Justin the Martyr and the Philosopher. Even though St. Justin has not developed a proper anthropology, because it was too early for such a performance, however he draw a few lines in this regard, that influenced later patristic tradition, also showing interest in humanist culture in general, because this culture has a pronounced character of continuity, keeping the principles of permanent value, principles earned through the efforts of the spirit and society over time. Man, in the conception of St. Justin the Martyr and the Philosopher, is a rational being comprised of two elements: body and soul. Taken separately, the two elements, body or soul, do not form the man, this being the union and unity of the two elements. Sf. Justin says that God, summoned to life and resurrection this entire assembly, that is the man, and not just a part of him. He considers man as being a miracle, if we take into account the small drop of seed which he derives from and which produces and develops the bones, nerves and flesh. As for the relationship between body and soul, St. Justin the Martyr and the Philosopher says that they are closely connected by the very act of creation.

  17. 风险投资家:Justin Bieber乐坛巨星贾斯汀·比伯

    Institute of Scientific and Technical Information of China (English)

    徐宝成

    2012-01-01

    他有着招牌式的金色头发和孩子般无邪的笑,他英俊,极具天赋,极为富有,而且每一分钱都是自己赚来的,从事自己喜欢的工作还吸引了无数人。这个人就是乐坛巨星——贾斯汀·比伯(Justin Bieber)。

  18. Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice.

    Science.gov (United States)

    Grieco, Anthony; Rzeczkowska, Paulina; Alm, Christina; Palmert, Mark R

    2013-01-30

    Genome-wide association studies recently identified 32 loci that associate with the age at menarche (AAM) in humans. Because the locus most robustly associated with AAM is in/near LIN28B, the goal of this study was to investigate how the Lin28 pathway might modulate pubertal timing by examining expression of Lin28b, and its homologue, Lin28a, across the pubertal transition in female mice. Quantitative reverse-transcriptase PCR data indicate that, prior to the onset of puberty, expression of both Lin28b and Lin28a decreases in the ovary, while expression of only Lin28a decreases in the hypothalamus; the expression of Lin28a increases after the onset of puberty in the pituitary. Immunohistochemistry in ovarian tissue verified that Lin28a protein levels decreased in parallel with gene expression. Although these data do not demonstrate cause and effect, they do suggest that decreased expression of Lin28a/Lin28b may facilitate the transition into puberty, consistent with previous data showing that overexpression of Lin28a in transgenic mice leads to delayed puberty. In addition, although Lin28b and/or Lin28a expression significantly decreased prior to puberty, neither Let-7a nor Let-7g miRNA levels changed significantly, raising the possibility that some effects of Lin28b and Lin28a within the hypothalamic-pituitary-gonadal (HPG) axis may be Let-7 miRNA independent. Subsequent studies, such as tissue and age specific modulation of Lin28b and Lin28a expression, could determine whether the expression patterns observed are responsible for modulating the onset of puberty and delineate further the role of this pathway in the HPG axis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. Dr. Lin Zhu's Clinical Experience in Treating Mental Disorders

    Institute of Scientific and Technical Information of China (English)

    Ma Xueqing; Wang Xinzhong

    2005-01-01

    @@ Mental disorders are mainly caused by the emotional factors. Chief physician Lin Zhu, a famous TCM doctor in Beijing, is very good at treating this kind of disorders. The following is a summary of Prof. Lin's experience in this aspect.

  20. Oncogenic Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms

    Science.gov (United States)

    Piskounova, Elena; Polytarchou, Christos; Thornton, James E.; Hagan, John P.; LaPierre, Robert J.; Pothoulakis, Charalabos; Iliopoulos, Dimitrios; Gregory, Richard I.

    2011-01-01

    Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUTase4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a TUTase-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts is restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors while Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function, and have implications for the development of new strategies for cancer therapy. PMID:22118463

  1. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms.

    Science.gov (United States)

    Piskounova, Elena; Polytarchou, Christos; Thornton, James E; LaPierre, Robert J; Pothoulakis, Charalabos; Hagan, John P; Iliopoulos, Dimitrios; Gregory, Richard I

    2011-11-23

    Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a Zcchc11-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors, whereas Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have implications for the development of new strategies for cancer therapy. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Lin28 promotes Her2 expression and Lin28/Her2 predicts poorer survival in gastric cancer.

    Science.gov (United States)

    Wang, Qinchuan; Zhou, Jichun; Guo, Jufeng; Teng, Rongyue; Shen, Jianguo; Huang, Yasheng; Xie, Shuduo; Wei, Qun; Zhao, Wenhe; Chen, Wenjun; Yuan, Xiaoming; Chen, Yongxia; Wang, Linbo

    2014-11-01

    The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (pLin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, pLin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.

  3. Analysis list: lin-42 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-42 + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-42.1.tsv h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-42.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-42.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-42..tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/.gml ...

  4. The Lin28/let-7 Axis Regulates Glucose Metabolism

    NARCIS (Netherlands)

    Zhu, Hao; Shyh-Chang, Ng; Segre, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2011-01-01

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both Lin28

  5. Lin Hairong:A Quiet Commentary

    Institute of Scientific and Technical Information of China (English)

    Jade; Franklin

    2007-01-01

    In looking at the works of Lin Hairong, one senses that the artist is seeking to capture life's tranquil moments; those fleeting glimpses of halcyon clarity and peace that remain uncontaminated by the frenetic pace of daily existence. Moments such as these have become few and far between however, in an age that the artist feels "is too quick to change".

  6. 泰勒与贾斯汀为赛琳娜争风吃醋!%Talyor and Justin Fight over Selena!

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    I was so excited when my BFF Selena Gomez came home to Texas for the weekend. But I was so shocked when she surprised me by bringing her friends Taylor Lautner and Justin Bieber with her. I gave them a shy smile as Selena pulled me upstairs.

  7. Analysis list: lin-15B [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-15B Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-15...B.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-15B.5.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/ce10/target/lin-15B.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-15B.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  8. Analysis list: lin-37 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-37 Embryo,Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-37.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-37.5.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/ce10/target/lin-37.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-37.Embryo....tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-37.Larvae.tsv http:

  9. 给比伯的弟妹当保姆%I Babysit for Justin Bieber's Sibings!

    Institute of Scientific and Technical Information of China (English)

    Fireheartz

    2012-01-01

    Brring! I snapped out of my Justin Bieber wedding daydream as the final bell rang in seventh period. Back to the reality of being just another random^3 JB fan. But I had bigger things to worry about--like how I was going to get enough money to buythe perfect dress for the eighth-grade dance.%贾斯汀·比伯是人气正旺的加拿大少年歌手。他不仅在音乐上有惊人的才华:创作、打鼓、跳舞、弹吉他、弹琴、小号样样行,而且长相很萌很帅气。他现在居住在美国并在美国发展。他的粉丝遍布世界各地。

  10. The LIN-15A and LIN-56 transcriptional regulators interact to negatively regulate EGF/Ras signaling in Caenorhabditis elegans vulval cell-fate determination.

    Science.gov (United States)

    Davison, Ewa M; Saffer, Adam M; Huang, Linda S; DeModena, John; Sternberg, Paul W; Horvitz, H Robert

    2011-03-01

    The restricted expression of epidermal growth factor (EGF) family ligands is important for proper development and for preventing cancerous growth in mammals. In Caenorhabditis elegans, the class A and B synthetic multivulva (synMuv) genes redundantly repress expression of lin-3 EGF to negatively regulate Ras-mediated vulval development. The class B synMuv genes encode proteins homologous to components of the NuRD and Myb-MuvB/dREAM transcriptional repressor complexes, indicating that they likely silence lin-3 EGF through chromatin remodeling. The two class A synMuv genes cloned thus far, lin-8 and lin-15A, both encode novel proteins. The LIN-8 protein is nuclear. We have characterized the class A synMuv gene lin-56 and found it to encode a novel protein that shares a THAP-like C(2)CH motif with LIN-15A. Both the LIN-56 and LIN-15A proteins localize to nuclei. Wild-type levels of LIN-56 require LIN-15A, and wild-type levels and/or localization of LIN-15A requires LIN-56. Furthermore, LIN-56 and LIN-15A interact in the yeast two-hybrid system. We propose that LIN-56 and LIN-15A associate in a nuclear complex that inhibits vulval specification by repressing lin-3 EGF expression.

  11. Comparison of the expression and function of Lin28A and Lin28B in colon cancer.

    Science.gov (United States)

    Wang, Tianzhen; He, Yan; Zhu, Yuanyuan; Chen, Mingwei; Weng, Mingjiao; Yang, Chao; Zhang, Yan; Ning, Ning; Zhao, Ran; Yang, Weiwei; Jin, Yinji; Li, Jing; Redpath, Riju James Rajkumar Ezakiel; Zhang, Lei; Jin, Xiaoming; Zhong, Zhaohua; Zhang, Fengmin; Wei, Yunwei; Shen, Guomin; Wang, Dong; Liu, Ying; Wang, Guangyu; Li, Xiaobo

    2016-11-29

    Lin28A and Lin28B are highly conserved RNA binding proteins with similar structure and functions. Recent studies demonstrated that both of them act as oncogenes and promote cancer progression. However, few researches compared the expression and functions of both oncogenes in human malignant tumors at same time. Additionally, although the expression and role of Lin28B in colon cancer is frequently reported, the expression and functions of Lin28A in colon cancer are largely unknown. In this study, we have systematically evaluated the expressional pattern, mutation status and correlation of both Lin28A and Lin28B in colon cancer tissues for the first time, and compared the roles of Lin28A and Lin28B in the proliferation, migration, invasion and apoptosis of colon cancer cells in vitro. We have showed that they are co-expressed and have functional similarities, however, the molecular mechanisms underlying their similar functions may not be identical. This study contributes to clarify the similarities and differences of Lin28A and Lin28B in colon cancer progression.

  12. LIN28A expression reduces sickling of cultured human erythrocytes.

    Science.gov (United States)

    de Vasconcellos, Jaira F; Fasano, Ross M; Lee, Y Terry; Kaushal, Megha; Byrnes, Colleen; Meier, Emily R; Anderson, Molly; Rabel, Antoinette; Braylan, Raul; Stroncek, David F; Miller, Jeffery L

    2014-01-01

    Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE) increased HbF, reduced beta (sickle)-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes.

  13. Analysis list: lin-13 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-13 Embryo,Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/...lin-13.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-13.5.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/ce10/target/lin-13.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-13.Embryo....tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-13.Larvae.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/ce10/colo/Embryo.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  14. Justine o la crítica política, ética y psicosocial de la sádica actualidad

    OpenAIRE

    Jorge Veraza Urtuzuástegui

    2011-01-01

    La obra del marqués de Sade es una crítica de la modernidad en sus diversos aspectos: economía, política y cultura, con énfasis en la crítica jurídica, ética y psicosocial que tiene como clave la conducta sexual y emocional. Todo esto destaca en su célebre novela Justine o los infortunios de la virtud. Este artículo busca contrarrestar las falsas interpretaciones que se han hecho de Justine y de la obra de Sade en general, que han terminado por desleer la valiosísima crítica que hace de la mo...

  15. Lin28 sustains early renal progenitors and induces Wilms tumor

    National Research Council Canada - National Science Library

    Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S; Zhu, Hao; Perez-Atayde, Antonio R; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q

    2014-01-01

    .... Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation...

  16. Analysis list: lin-39 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-39 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-39....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-39.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-39.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-39.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  17. Analysis list: lin-53 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-53 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-53....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-53.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-53.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-53.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  18. Analysis list: lin-11 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-11 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-11....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-11.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-11.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-11.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  19. Analysis list: lin-52 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-52 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-52....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-52.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-52.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-52.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  20. Analysis list: lin-9 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-9 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-9.1....tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-9.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-9.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-9.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  1. Analysis list: lin-54 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-54 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-54....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-54.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-54.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-54.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  2. Analysis list: lin-61 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-61 Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-61....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-61.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/li...n-61.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-61.Larvae.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  3. LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty

    Directory of Open Access Journals (Sweden)

    Koivu Rosanna

    2011-09-01

    Full Text Available Abstract Background Pubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP probably exist, as cases of familial ICPP have been reported. Mutations in KISS1 and KISSR, coding for kisspeptin and its receptor, involved in GnRH secretion and puberty onset, have been suggested causative for monogenic ICPP. Variation in LIN28B was associated with timing of puberty in genome-wide association (GWA studies. LIN28B is a human ortholog of the gene that controls, through microRNAs, developmental timing in C. elegans. In addition, Lin28a transgenic mice manifest the puberty phenotypes identified in the human GWAS. Thus, both LIN28B and LIN28A may have a role in pubertal development and are good candidate genes for monogenic ICPP. Methods Thirty girls with ICPP were included in the study. ICPP was defined by pubertal onset before 8 yrs of age, and a pubertal LH response to GnRH testing. The coding regions of LIN28B, LIN28A, KISS1, and KISS1R were sequenced. The missense change in LIN28B was also screened in 132 control subjects. Results No rare variants were detected in KISS1 or KISS1R in the 30 subjects with ICPP. In LIN28B, one missense change, His199Arg, was found in one subject with ICPP. However, this variant was also detected in one of the 132 controls. No variation in LIN28A was found. Conclusions We did not find any evidence that mutations in LIN28B or LIN28A would underlie ICPP. In addition, we confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

  4. LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty.

    Science.gov (United States)

    Tommiska, Johanna; Sørensen, Kaspar; Aksglaede, Lise; Koivu, Rosanna; Puhakka, Lea; Juul, Anders; Raivio, Taneli

    2011-09-22

    Pubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP) is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP probably exist, as cases of familial ICPP have been reported. Mutations in KISS1 and KISSR, coding for kisspeptin and its receptor, involved in GnRH secretion and puberty onset, have been suggested causative for monogenic ICPP. Variation in LIN28B was associated with timing of puberty in genome-wide association (GWA) studies. LIN28B is a human ortholog of the gene that controls, through microRNAs, developmental timing in C. elegans. In addition, Lin28a transgenic mice manifest the puberty phenotypes identified in the human GWAS. Thus, both LIN28B and LIN28A may have a role in pubertal development and are good candidate genes for monogenic ICPP. Thirty girls with ICPP were included in the study. ICPP was defined by pubertal onset before 8 yrs of age, and a pubertal LH response to GnRH testing. The coding regions of LIN28B, LIN28A, KISS1, and KISS1R were sequenced. The missense change in LIN28B was also screened in 132 control subjects. No rare variants were detected in KISS1 or KISS1R in the 30 subjects with ICPP. In LIN28B, one missense change, His199Arg, was found in one subject with ICPP. However, this variant was also detected in one of the 132 controls. No variation in LIN28A was found. We did not find any evidence that mutations in LIN28B or LIN28A would underlie ICPP. In addition, we confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

  5. Lin28a regulates germ cell pool size and fertility.

    Science.gov (United States)

    Shinoda, Gen; De Soysa, T Yvanka; Seligson, Marc T; Yabuuchi, Akiko; Fujiwara, Yuko; Huang, Pei Yi; Hagan, John P; Gregory, Richard I; Moss, Eric G; Daley, George Q

    2013-05-01

    Overexpression of LIN28A is associated with human germ cell tumors and promotes primordial germ cell (PGC) development from embryonic stem cells in vitro and in chimeric mice. Knockdown of Lin28a inhibits PGC development in vitro, but how constitutional Lin28a deficiency affects the mammalian reproductive system in vivo remains unknown. Here, we generated Lin28a knockout (KO) mice and found that Lin28a deficiency compromises the size of the germ cell pool in both males and females by affecting PGC proliferation during embryogenesis. Interestingly however, in Lin28a KO males, the germ cell pool partially recovers during postnatal expansion, while fertility remains impaired in both males and females mated to wild-type mice. Embryonic overexpression of let-7, a microRNA negatively regulated by Lin28a, reduces the germ cell pool, corroborating the role of the Lin28a/let-7 axis in regulating the germ lineage. Copyright © 2013 AlphaMed Press.

  6. The Lin28/let-7 Axis Regulates Glucose Metabolism

    NARCIS (Netherlands)

    Zhu, Hao; Shyh-Chang, Ng; Segre, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2011-01-01

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both

  7. Lin28 enhances tissue repair by reprogramming cellular metabolism.

    Science.gov (United States)

    Shyh-Chang, Ng; Zhu, Hao; Yvanka de Soysa, T; Shinoda, Gen; Seligson, Marc T; Tsanov, Kaloyan M; Nguyen, Liem; Asara, John M; Cantley, Lewis C; Daley, George Q

    2013-11-07

    Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics. PAPERCLIP: Copyright © 2013 Elsevier Inc. All rights reserved.

  8. LIN28 expression in rat spinal cord after injury.

    Science.gov (United States)

    Yue, Ying; Zhang, Dongmei; Jiang, Shengyang; Li, Aihong; Guo, Aisong; Wu, Xinming; Xia, Xiaopeng; Cheng, Hongbing; Tao, Tao; Gu, Xingxing

    2014-05-01

    LIN28, an RNA-binding protein, is known to be involved in the regulation of many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. However, its expression and function in central nervous system still unclear. In this study, we performed an acute spinal cord contusion injury (SCI) model in adult rats and investigated the dynamic changes of LIN28 expression in spinal cord. Western blot and immunohistochemistry analysis revealed that LIN28 was present in normal spinal cord. It gradually increased, reached a peak at 3 day, and then nearly declined to the basal level at 14 days after SCI. Double immunofluorescence staining showed that LIN28 immunoreactivity was found in neurons, astrocytes and a handful of microglia. Interestingly, LIN28 expression was increased predominantly in astrocytes but not in neurons. Moreover, the colocalization of LIN28 and proliferating cell nuclear antigen was detected after injury. Western blot showed that LIN28 participated in lipopolysaccharide (LPS) induced astrocytes inflammatory responses by NF-κB signaling pathway. These results suggested that LIN28 may be involved in the pathologic process of SCI, and further research is needed to have a good understanding of its function and mechanism.

  9. Analysis list: lin-35 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available lin-35 Adult,Larvae + ce10 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/l...in-35.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/target/lin-35.5.tsv http://dbarchive.bioscienced...bc.jp/kyushu-u/ce10/target/lin-35.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-35.Adult.t...sv,http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/lin-35.Larvae.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/ce10/colo/Adult.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/colo/Larvae.gml ...

  10. C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/Frizzled in Wnt signaling.

    Science.gov (United States)

    Inoue, Takao; Oz, Helieh S; Wiland, Debra; Gharib, Shahla; Deshpande, Rashmi; Hill, Russell J; Katz, Wendy S; Sternberg, Paul W

    2004-09-17

    Wnt proteins are intercellular signals that regulate various aspects of animal development. In Caenorhabditis elegans, mutations in lin-17, a Frizzled-class Wnt receptor, and in lin-18 affect cell fate patterning in the P7.p vulval lineage. We found that lin-18 encodes a member of the Ryk/Derailed family of tyrosine kinase-related receptors, recently found to function as Wnt receptors. Members of this family have nonactive kinase domains. The LIN-18 kinase domain is dispensable for LIN-18 function, while the Wnt binding WIF domain is required. We also found that Wnt proteins LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning. Genetic interactions indicate that LIN-17 and LIN-18 function independently of each other in parallel pathways, and different ligands display different receptor specificities. Thus, two independent Wnt signaling pathways, one employing a Ryk receptor and the other a Frizzled receptor, function in parallel to regulate cell fate patterning in the C. elegans vulva.

  11. The Lin28/let-7 axis regulates glucose metabolism.

    Science.gov (United States)

    Zhu, Hao; Shyh-Chang, Ng; Segrè, Ayellet V; Shinoda, Gen; Shah, Samar P; Einhorn, William S; Takeuchi, Ayumu; Engreitz, Jesse M; Hagan, John P; Kharas, Michael G; Urbach, Achia; Thornton, James E; Triboulet, Robinson; Gregory, Richard I; Altshuler, David; Daley, George Q

    2011-09-30

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. DNA methylation of the LIN28 pseudogene family.

    Science.gov (United States)

    Davis, Aaron P; Benninghoff, Abby D; Thomas, Aaron J; Sessions, Benjamin R; White, Kenneth L

    2015-04-11

    DNA methylation directs the epigenetic silencing of selected regions of DNA, including the regulation of pseudogenes, and is widespread throughout the genome. Pseudogenes are decayed copies of duplicated genes that have spread throughout the genome by transposition. Pseudogenes are transcriptionally silenced by DNA methylation, but little is known about how pseudogenes are targeted for methylation or how methylation levels are maintained in different tissues. We employed bisulfite next generation sequencing to examine the methylation status of the LIN28 gene and four processed pseudogenes derived from LIN28. The objective was to determine whether LIN28 pseudogenes maintain the same pattern of methylation as the parental gene or acquire a methylation pattern independent of the gene of origin. In this study, we determined that the methylation status of LIN28 pseudogenes does not resemble the pattern evident for the LIN28 gene, but rather these pseudogenes appear to acquire methylation patterns independent of the parental gene. Furthermore, we observed that methylation levels of the examined pseudogenes correlate to the location of insertion within the genome. LIN28 pseudogenes inserted into gene bodies were highly methylated in all tissues examined. In contrast, pseudogenes inserted into genomic regions that are not proximal to genes were differentially methylated in various tissue types. Our analysis suggests that Lin28 pseudogenes do not acquire patterns of tissue-specific methylation as for the parental gene, but rather are methylated in patterns specific to the local genomic environment into which they were inserted.

  13. RNA-binding protein Lin28 in cancer and immunity.

    Science.gov (United States)

    Jiang, Shuai; Baltimore, David

    2016-05-28

    The highly conserved RNA-binding protein, Lin28, is involved in many biological processes, including development, reprogramming, pluripotency, and metabolism. Importantly, Lin28 functions as an oncogene, promoting tumor progression and metastasis in various human cancers. Lin28 can regulate gene expression either by directly binding to mRNAs or by blocking microRNA biogenesis, and the underlying mechanisms include Let-7-dependent and Let-7-independent modes of action. Recent evidence shows that Lin28 also plays a fundamental role in immunity. The roles of Lin28 in disease are complex and require characterization of its physiological functions in cancer and immunological contexts. Here we review emerging information on the role of Lin28 in cancer and immunity and the molecular mechanisms it uses. We discuss our present knowledge of the system and highlight remaining mysteries related to the functions of this small RNA-binding protein. This knowledge may lead to Lin28 becoming a diagnostic marker for cancer or immune-related diseases and a possible therapeutic target.

  14. A Small-Molecule Inhibitor of Lin28.

    Science.gov (United States)

    Roos, Martina; Pradère, Ugo; Ngondo, Richard P; Behera, Alok; Allegrini, Sara; Civenni, Gianluca; Zagalak, Julian A; Marchand, Jean-Rémy; Menzi, Mirjam; Towbin, Harry; Scheuermann, Jörg; Neri, Dario; Caflisch, Amedeo; Catapano, Carlo V; Ciaudo, Constance; Hall, Jonathan

    2016-10-21

    New discoveries in RNA biology underscore a need for chemical tools to clarify their roles in pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an RNA binding protein (RBP) Lin28, which docks onto a conserved sequence in let-7 precursor RNA molecules and prevents their maturation. Thus, the Lin28/let-7 interaction might be an attractive drug target, if not for the well-known difficulty in targeting RNA-protein interactions with drugs. Here, we describe a protein/RNA FRET assay using a GFP-Lin28 donor and a black-hole quencher (BHQ)-labeled let-7 acceptor, a fluorescent protein/quencher combination which is rarely used in screening despite favorable spectral properties. We tested 16 000 molecules and identified N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, which blocked the Lin28/let-7 interaction, rescued let-7 processing and function in Lin28-expressing cancer cells, induced differentiation of mouse embryonic stem cells, and reduced tumor-sphere formation by 22Rv1 and Huh7 cells. A biotinylated derivative captured Lin28 from cell lysates consistent with an on-target mechanism in cells, though the compound also showed some activity against bromodomains in selectivity assays. The Lin28/let-7 axis is presently of high interest not only for its role as a bistable switch in stem-cell biology but also because of its prominent roles in numerous diseases. We anticipate that much can be learned from the use of this first reported small molecule antagonist of Lin28, including the potential of the Lin28/let-7 interaction as a new drug target for selected cancers. Furthermore, this approach to assay development may be used to identify antagonists of other RBP/RNA interactions suspected to be operative in pathophysiological mechanisms.

  15. 原位杂交检测lin-28 mRNA在 Caenorhabditis elegans中的分布%Distribution of lin-28 mRNA in Wild-type and Mutants of C. elegans Via in situ Hybridization

    Institute of Scientific and Technical Information of China (English)

    杨玉荣; 郑卫玲

    2008-01-01

    利用原位杂交检测了异时性基因lin-28 mRNA在野生型和lin-4,lin-14突变体以及lin-4,lin-14双突变体中的分布,发现lin-28 mRNA在胚胎和成虫生殖腺中存在.还发现lin-4突变不改变lin-28 mRNA分布,证明了lin-28表达独立于lin-4抑制通路的存在.

  16. On the low regularity of the Benney-Lin equation

    Science.gov (United States)

    Chen, Wengu; Li, Junfeng

    2008-03-01

    We consider the low regularity of the Benney-Lin equation ut+uux+uxxx+[beta](uxx+uxxxx)+[eta]uxxxxx=0. We established the global well posedness for the initial value problem of Benney-Lin equation in the Sobolev spaces for 0[greater-or-equal, slanted]s>-2, improving the well-posedness result of Biagioni and Linares [H.A. Biaginoi, F. Linares, On the Benney-Lin and Kawahara equation, J. Math. Anal. Appl. 211 (1997) 131-152]. For s<-2 we also prove some ill-posedness issues.

  17. 原位杂交检测历lin-28mRNA在Caenorhabditis elegans中的分布

    Institute of Scientific and Technical Information of China (English)

    杨玉荣; 郑卫玲

    2008-01-01

    利用原位杂交检测了异时性基因lin-28mRNA在野生型和lin-4,lin-14突变体以及lin-4,lin-14双突变体中的分布,发现lin-28mlLNA在胚胎和成虫生殖腺中存在.还发现lin-4突变不改变lin-28mlLNA分布,证明了lin-28表达独立于lin-4抑制通路的存在.

  18. In vitro expansion of Lin{sup +} and Lin{sup −} mononuclear cells from human peripheral blood

    Energy Technology Data Exchange (ETDEWEB)

    Norhaiza, H. Siti; Zarina, Z. A. Intan; Hisham, Z. A. Shahrul [School of Bioscience and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, Selangor (Malaysia); Rohaya, M. A. W. [Department of Orthodontics, Faculty of Dentistry, Universiti Kebangsaan Malaysia, 50300, Kuala Lumpur (Malaysia)

    2013-11-27

    Haematopoietic stem cells (HSCs) are used in the therapy of blood disorders due to the ability of these cells to reconstitute haematopoietic lineage cells when transplanted into myeloablative recipients. However, substantial number of cells is required in order for the reconstitution to take place. Since HSCs present in low frequency, larger number of donor is required to accommodate the demand of transplantable HSCs. Therefore, in vitro expansion of HSCs will have profound impact on clinical purposes. The aim of this study was to expand lineage negative (Lin{sup −}) stem cells from human peripheral blood. Total peripheral blood mononuclear cells (PBMNCs) were fractionated from human blood by density gradient centrifugation. Subsequently, PBMNCs were subjected to magnetic assisted cell sorter (MACS) which depletes lineage positive (Lin{sup +}) mononuclear cells expressing lineage positive markers such as CD2, CD3, CD11b, CD14, CD15, CD16, CD19, CD56, CD123, and CD235a to obtained Lin{sup −} cell population. The ability of Lin{sup +} and Lin{sup −} to survive in vitro was explored by culturing both cell populations in complete medium consisting of Alpha-Minimal Essential Medium (AMEM) +10% (v/v) Newborn Calf Serum (NBCS)+ 2% (v/v) pen/strep. In another experiment, Lin{sup +} and Lin{sup −} were cultured with complete medium supplemented with 10ng/mL of the following growth factors: stem cell factor (SCF), interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF), 2IU/mL of Erythropoietin (Epo) and 20ng/mL of IL-6. Three samples were monitored in static culture for 22 days. The expansion potential was assessed by the number of total viable cells, counted by trypan blue exclusion assay. It was found that Lin{sup +} mononuclear cells were not able to survive either in normal proliferation medium or proliferation medium supplemented with cytokines. Similarly, Lin{sup −} stem cells were not able to survive in proliferation medium however

  19. The signal pathway of Lin28 and tumor%Lin28信号通路与肿瘤

    Institute of Scientific and Technical Information of China (English)

    荚耘路; 吕可真; 林娜; 胡文献

    2014-01-01

    Lin28 is a highly conserved RNA-binding protein that has an important role in human body development, metabolism, and tumorigenesis. Previous studies have found that the activation of Lin28 can suppress the maturity of let-7 miRNA in stem cells and promote the proliferation of stem cells by upregulating cell-cycle related genes, such as cyclins A and B. Other mechanisms underlying the activation of Lin28 can selectively block the processes of pre-let-7 miRNA in embryonic stem cells and ultimately promote tumori-genesis. In addition, Lin28 affects the occurrence, development, and prognosis of cancer by inhibiting the differentiation and maturation of miRNA and by moderating the expression of some cell-cycle related genes. Lin28 has an important function in the tumor's tolerance of chemotherapy and radiotherapy. We review the physiological function of Lin28 in tumors and its function in tumor treatment.%Lin28是一种结构上高度保守的RNA结合蛋白,其在机体正常生长发育代谢及某些疾病状态,如肿瘤发生发展中有重要作用。近年的研究发现,Lin28在机体中的过表达能够抑制let-7 miRNA的功能,并上调某些细胞周期相关基因如cyclin A、cyclin B等的表达,从而促进干细胞的增殖。在人类恶性肿瘤细胞中,Lin28的激活能选择性地阻断原始let-7 miRNA的加工成熟并最终促进肿瘤的发生;Lin28在肿瘤疾病进程中的其他作用机制包括:通过抑制肿瘤相关microRNA的分化成熟、上调细胞周期相关基因的表达影响肿瘤的发展及预后。另外,Lin28在肿瘤放化疗耐受相关研究中的重要作用日益凸显。为此,本文对Lin28的相关生理功能和其在肿瘤发生发展的相关机制及治疗前景做一综述。

  20. lin-8, which antagonizes Caenorhabditis elegans Ras-mediated vulval induction, encodes a novel nuclear protein that interacts with the LIN-35 Rb protein.

    Science.gov (United States)

    Davison, Ewa M; Harrison, Melissa M; Walhout, Albertha J M; Vidal, Marc; Horvitz, H Robert

    2005-11-01

    Ras-mediated vulval development in C. elegans is inhibited by the functionally redundant sets of class A, B, and C synthetic Multivulva (synMuv) genes. Three of the class B synMuv genes encode an Rb/DP/E2F complex that, by analogy with its mammalian and Drosophila counterparts, has been proposed to silence genes required for vulval specification through chromatin modification and remodeling. Two class A synMuv genes, lin-15A and lin-56, encode novel nuclear proteins that appear to function as a complex. We show that a third class A synMuv gene, lin-8, is the defining member of a novel C. elegans gene family. The LIN-8 protein is nuclear and can interact physically with the product of the class B synMuv gene lin-35, the C. elegans homolog of mammalian Rb. LIN-8 likely acts with the synMuv A proteins LIN-15A and LIN-56 in the nucleus, possibly in a protein complex with the synMuv B protein LIN-35 Rb. Other LIN-8 family members may function in similar complexes in different cells or at different stages. The nuclear localization of LIN-15A, LIN-56, and LIN-8, as well as our observation of a direct physical interaction between class A and class B synMuv proteins, supports the hypothesis that the class A synMuv genes control vulval induction through the transcriptional regulation of gene expression.

  1. How does Lin28 let-7 control development and disease?

    Science.gov (United States)

    Thornton, James E.; Gregory, Richard I.

    2012-01-01

    One of the most ancient and highly conserved microRNAs (miRNAs), the let-7 family, has gained notoriety owing to its regulation of stem cell differentiation, essential role in normal development, as well as its tumor suppressor function. Mechanisms controlling let-7 expression have recently been uncovered, specifically the role of the RNA-binding protein Lin28 – a key developmental regulator - in blocking let-7 biogenesis. This review focuses on our current understanding of the Lin28-mediated control of let-7 maturation and highlights the central role of Lin28 in stem cell biology, development, control of glucose metabolism, and dysregulation in human disease. Manipulating the Lin28 pathway for the precise control of let-7 expression may therefore provide novel therapeutic opportunities for cancer and other diseases. PMID:22784697

  2. The Policy Issues in Lin an Modei Forest of China

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Based on the analysis on policy such as property rights, tax and administration fee, harvesting and circulation of forest products in Lin 'an Modei Forest, some policy issues in the development of Lin 'an Model Forest towards sustainable forest management were raised: (1) The level of timber tax and fee is quite high and there are many kinds of taxes and fees such as fees for forest silviculture, forestry maintenance, forest protection, city construction, town-service, additional fee for education and o...

  3. LIN28A expression reduces sickling of cultured human erythrocytes.

    Directory of Open Access Journals (Sweden)

    Jaira F de Vasconcellos

    Full Text Available Induction of fetal hemoglobin (HbF has therapeutic importance for patients with sickle cell disease (SCD and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+ sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE increased HbF, reduced beta (sickle-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes.

  4. The LIN28/let-7 Pathway in Cancer.

    Science.gov (United States)

    Balzeau, Julien; Menezes, Miriam R; Cao, Siyu; Hagan, John P

    2017-01-01

    Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.

  5. Lin-28 regulates oogenesis and muscle formation in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Vassilis Stratoulias

    Full Text Available Understanding the control of stem cell (SC differentiation is important to comprehend developmental processes as well as to develop clinical applications. Lin28 is a conserved molecule that is involved in SC maintenance and differentiation by regulating let-7 miRNA maturation. However, little is known about the in vivo function of Lin28. Here, we report critical roles for lin-28 during oogenesis. We found that let-7 maturation was increased in lin-28 null mutant fly ovaries. We showed that lin-28 null mutant female flies displayed reduced fecundity, due to defects in egg chamber formation. More specifically, we demonstrated that in mutant ovaries, the egg chambers fuse during early oogenesis resulting in abnormal late egg chambers. We also showed that this phenotype is the combined result of impaired germline SC differentiation and follicle SC differentiation. We suggest a model in which these multiple oogenesis defects result from a misregulation of the ecdysone signaling network, through the fine-tuning of Abrupt and Fasciclin2 expression. Our results give a better understanding of the evolutionarily conserved role of lin-28 on GSC maintenance and differentiation.

  6. Drosha mediates destabilization of Lin28 mRNA targets.

    Science.gov (United States)

    Qiao, Chong; Ma, Jing; Xu, Jie; Xie, Mingyi; Ma, Wei; Huang, Yingqun

    2012-10-01

    Lin28 plays important roles in development, stem cell maintenance, oncogenesis and metabolism. As an RNA-binding protein, it blocks the biogenesis primarily of let-7 family miRNAs and also promotes translation of a cohort of mRNAs involved in cell growth, metabolism and pluripotency, likely through recognition of distinct sequence and structural motifs within mRNAs. Here, we show that one such motif, shared by multiple Lin28-responsive elements (LREs) present in Lin28 mRNA targets also participates in a Drosha-dependent regulation and may contribute to destabilization of its cognate mRNAs. We further show that the same mutations in the LREs known to abolish Lin28 binding and stimulation of translation also abrogate Drosha-dependent mRNA destabilization, and that this effect is independent of miRNAs, uncovering a previously unsuspected coupling between Drosha-dependent destabilization and Lin28-mediated regulation. Thus, Lin28-dependent stimulation of translation of target mRNAs may, in part, serve to compensate for their intrinsic instability, thereby ensuring optimal levels of expression of genes critical for cell viability, metabolism and pluripotency.

  7. Lin28 sustains early renal progenitors and induces Wilms tumor.

    Science.gov (United States)

    Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S; Zhu, Hao; Perez-Atayde, Antonio R; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q

    2014-05-01

    Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.

  8. Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferation of hepatoma cells.

    Science.gov (United States)

    You, X; Liu, F; Zhang, T; Lv, N; Liu, Q; Shan, C; Du, Y; Kong, G; Wang, T; Ye, L; Zhang, X

    2014-01-23

    Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt -235/-66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.

  9. EFECTO DE EXTRACTOS ACUOSOS DE Helianthus annuus Lin. SOBRE EL CRECIMIENTO DE Solanum lycopersicum Lin.

    Directory of Open Access Journals (Sweden)

    Yaniuska González Perigó

    2015-01-01

    Full Text Available Con el objetivo de determinar el efecto de extractos acuosos de Helianthus annuus Lin. sobre el crecimiento de Solanum lycopersicum Lin, se tomaron muestras de raíz y hojas de plantas recolectadas de un sistema de policultivo ubicado en un agroecosistema montañoso. Los extractos acuosos de girasol se obtuvieron a partir de raíz y hojas de plantas recolectadas durante dos años. Se evaluaron los efectos de estos extractos sobre la germinación, longitud de la radícula y del hipocótilo de semillas de tomate certificadas, para ello se ejecutaron nueve tratamientos con cuatro repeticiones dispuestos en placas Petri. Los extractos de raíz de girasol a los 15, 30 y 45 días y de hojas a los 75 y 90 días de desarrollo inhibieron la germinación de las semillas de tomate y el crecimiento de la radícula y el hipocótilo. Los extractos de raíz de girasol con 75 y 90 días, estimularon el crecimiento de la radícula y del hipocótilo del tomate. Estos resultados demuestran que el girasol produce sustancias químicas que inhiben el crecimiento del tomate y no se recomienda asociar estos dos cultivos de forma simultánea.

  10. LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency.

    Science.gov (United States)

    Zhang, Jin; Ratanasirintrawoot, Sutheera; Chandrasekaran, Sriram; Wu, Zhaoting; Ficarro, Scott B; Yu, Chunxiao; Ross, Christian A; Cacchiarelli, Davide; Xia, Qing; Seligson, Marc; Shinoda, Gen; Xie, Wen; Cahan, Patrick; Wang, Longfei; Ng, Shyh-Chang; Tintara, Supisara; Trapnell, Cole; Onder, Tamer; Loh, Yuin-Han; Mikkelsen, Tarjei; Sliz, Piotr; Teitell, Michael A; Asara, John M; Marto, Jarrod A; Li, Hu; Collins, James J; Daley, George Q

    2016-07-07

    The RNA-binding proteins LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, but their exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can function effectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of both endogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In human fibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during the transition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28B facilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlighted roles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and in regulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds to mRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus, LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, and stem cell metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. The heterochronic genes lin-28a and lin-28b play an essential and evolutionarily conserved role in early zebrafish development.

    Directory of Open Access Journals (Sweden)

    Yasuo Ouchi

    Full Text Available The Caenorhabditis elegans heterochronic gene pathway, which consists of a set of regulatory genes, plays an important regulatory role in the timing of stage-specific cell lineage development in nematodes. Research into the heterochronic gene pathway gave rise to landmark microRNA (miRNA studies and showed that these genes are important in stem cell and cancer biology; however, their functions in vertebrate development are largely unknown. To elucidate the function of the heterochronic gene pathway during vertebrate development, we cloned the zebrafish homologs of the C. elegans let-7 miRNA-binding protein, Lin-28, and analyzed their function in zebrafish development. The zebrafish genome contains two Lin28-related genes, lin-28a and lin-28b. Similar to mammalian Lin28 proteins, both zebrafish Lin-28a and Lin-28b have a conserved cold-shock domain and a pair of CCHC zinc finger domains, and are ubiquitously expressed during early embryonic development. In a reciprocal fashion, the expression of downstream heterochronic genes, let-7 and lin-4/miR-125 miRNA, occurred subsequent to lin-28 expression. The knockdown of Lin-28a or Lin-28b function by morpholino microinjection into embryos resulted in severe cell proliferation defects during early morphogenesis. We found that the expression of let-7 miRNA was upregulated and its downstream target gene, lin-41, was downregulated in these embryos. Interestingly, the expression of miR-430, a key regulator of maternal mRNA decay, was downregulated in lin-28a and lin-28b morphant embryos, suggesting a role for Lin-28 in the maternal-to-zygotic transition in zebrafish. Taken together, our results suggest an evolutionarily conserved and pivotal role of the heterochronic gene pathway in early vertebrate embryogenesis.

  12. Lin28 and let-7 in cell metabolism and cancer.

    Science.gov (United States)

    Nguyen, Liem H; Zhu, Hao

    2015-01-01

    Malignant cells exhibit major metabolic alterations. The regulatory gene networks that regulate metabolism and the impact of these alterations on overall cellular fitness deserve further exploration. The let-7 microRNAs and their antagonists, the Lin28 RNA-binding proteins, are well-known for controlling the timing of embryonic development. This pathway has recently been shown to regulate glucose metabolism in adult mice and to reprogram metabolism during tissue injury and repair. In addition, many lines of evidence have established that Lin28 is an oncogene that drives tumorigenesis in part by suppressing let-7. The metabolic underpinnings of this oncogenic program are just beginning to be uncovered. Here, we will review the current understanding of how Lin28 exerts regenerative and oncogenic effects through metabolic mechanisms.

  13. The Analysis of Lin Yutang’s Humor

    Institute of Scientific and Technical Information of China (English)

    陈晓琴

    2014-01-01

    Lin Yutang is called the master humorist in China. He advocates humor and spiritual literature in his maga-zine Lun Yu (Analects) which attracts essays and readership. His informal but polished style in both Chinese and English makes him one of the most influential writers of his generation, and his compilations and translations of classic Chinese texts into English are bestsellers in the West. Humor is a distinctive feature in his works. In his book, he uses humor as he sees appropriate, and through humor he criticizes social realities, depicts characters and introduces original expressions, etc. His humor can be related to some aspects in his life. In this paper, I will briefly analysis Lin's sense of humor and how Lin' applies humor in his works.

  14. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer.

    Science.gov (United States)

    Wang, Tianzhen; Wang, Guangyu; Hao, Dapeng; Liu, Xi; Wang, Dong; Ning, Ning; Li, Xiaobo

    2015-06-30

    RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed.

  15. Sex-specific regulation of weight and puberty by the Lin28/let-7 axis.

    Science.gov (United States)

    Corre, Christina; Shinoda, Gen; Zhu, Hao; Cousminer, Diana L; Crossman, Christine; Bellissimo, Christian; Goldenberg, Anna; Daley, George Q; Palmert, Mark R

    2016-03-01

    Growth and pubertal timing differ in boys and girls. Variants in/near LIN28B associate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response to Lin28b perturbation have been detected in mice, and overexpression of Lin28a has been shown to alter pubertal timing in female mice. To investigate further how Lin28a and Lin28b affect growth and puberty in both males and females, we evaluated Lin28b loss-of-function (LOF) mice and Lin28a gain-of-function (GOF) mice. Because both Lin28a and Lin28b can act via the conserved microRNA let-7, we also examined let-7 GOF mice. As reported previously, Lin28b LOF led to lighter body weights only in male mice while Lin28a GOF yielded heavier mice of both sexes. Let-7 GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). Male Lin28b LOF and male let-7 GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and female Lin28a GOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation by Lin28a, Lin28b, and let-7, in which Lin28b and let-7 can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans. © 2016 Society for Endocrinology.

  16. Lin28 promotes the proliferative capacity of neural progenitor cells in brain development.

    Science.gov (United States)

    Yang, Mei; Yang, Si-Lu; Herrlinger, Stephanie; Liang, Chen; Dzieciatkowska, Monika; Hansen, Kirk C; Desai, Ridham; Nagy, Andras; Niswander, Lee; Moss, Eric G; Chen, Jian-Fu

    2015-05-01

    Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development. © 2015. Published by The Company of Biologists Ltd.

  17. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development.

    Science.gov (United States)

    Huang, L S; Tzou, P; Sternberg, P W

    1994-01-01

    During Caenorhabditis elegans vulval development, an inductive signal from the anchor cell stimulates three of the six vulval precursor cells (VPCs) to adopt vulval rather than nonvulval epidermal fates. Genes necessary for this induction include the lin-3 growth factor, the let-23 receptor tyrosine kinase, and let-60 ras. lin-15 is a negative regulator of this inductive pathway. In lin-15 mutant animals, all six VPCs adopt vulval fates, even in the absence of inductive signal. Previous genetic studies suggested that lin-15 is a complex locus with two independently mutable activities, A and B. We have cloned the lin-15 locus by germline transformation and find that it encodes two nonoverlapping transcripts that are transcribed in the same direction. The downstream transcript encodes the lin-15A function; the upstream transcript encodes the lin-15B function. The predicted lin-15A and lin-15B proteins are novel and hydrophilic. We have identified a molecular null allele of lin-15 and have used it to analyze the role of lin-15 in the signaling pathway. We find that lin-15 acts upstream of let-23 and in parallel to the inductive signal. Images PMID:8054684

  18. File list: Oth.Lar.05.lin-35.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lar.05.lin-35.AllCell ce10 TFs and others lin-35 Larvae SRX331086,SRX233462,SRX...059240,SRX233461,SRX331088,SRX059241 http://dbarchive.biosciencedbc.jp/kyushu-u/ce10/assembled/Oth.Lar.05.lin-35.AllCell.bed ...

  19. Lin28a--boost your energy for youthful regeneration.

    Science.gov (United States)

    Burkhalter, Martin D; Morita, Yohei; Rudolph, Karl Lenhard

    2014-01-07

    The regenerative capacity of most tissues declines dramatically after embryonic development and during post-natal life. The underlying mechanisms of this phenomenon are incompletely understood. In a recent issue of Cell, Shyh-Chang and colleagues provide experimental evidence that Lin28 prolongs youthful regenerative capacity by increasing oxidative glucose metabolism (Shyh-Chang et al, 2013).

  20. The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse

    Directory of Open Access Journals (Sweden)

    Kaestner Klaus H

    2009-06-01

    Full Text Available Abstract Background Life-long production of spermatozoa depends on spermatogonial stem cells. Spermatogonial stem cells exist among the most primitive population of germ cells – undifferentiated spermatogonia. Transplantation experiments have demonstrated the functional heterogeneity of undifferentiated spermatogonia. Although the undifferentiated spermatogonia can be topographically divided into As (single, Apr (paired, and Aal (aligned spermatogonia, subdivision of this primitive cell population using cytological markers would greatly facilitate characterization of their functions. Results In the present study, we show that LIN28, a pluripotency factor, is specifically expressed in undifferentiated spermatogonia (As, Apr, and Aal in mouse. Ngn3 also specifically labels undifferentiated spermatogonia. We used Ngn3-GFP knockin mice, in which GFP expression is under the control of all Ngn3 transcription regulatory elements. Remarkably, Ngn3-GFP is only expressed in ~40% of LIN28-positive As (single cells. The percentage of Ngn3-GFP-positive clusters increases dramatically with the chain length of interconnected spermatogonia. Conclusion Our study demonstrates that LIN28 specifically marks undifferentiated spermatogonia in mice. These data, together with previous studies, suggest that the LIN28-expressing undifferentiated spermatogonia exist as two subpopulations: Ngn3-GFP-negative (high stem cell potential and Ngn3-GFP-positive (high differentiation commitment. Furthermore, Ngn3-GFP-negative cells are found in chains of Ngn3-GFP-positive spermatogonia, suggesting that cells in the Aal spermatogonia could revert to a more primitive state.

  1. Lin28: Primal Regulator of Growth and Metabolism in Stem Cells

    Science.gov (United States)

    Shyh-Chang, Ng; Daley, George Q.

    2013-01-01

    In recent years, the highly conserved Lin28 RNA-binding proteins have emerged as factors that define stemness in several tissue lineages. Lin28 proteins repress let-7 microRNAs and influence mRNA translation, thereby regulating the self-renewal of mammalian embryonic stem cells. Subsequent discoveries revealed that Lin28a and Lin28b are also important in organismal growth and metabolism, tissue development, somatic reprogramming and cancer. In this Review, we discuss the Lin28 pathway and its regulation, outline its roles in stem cells, tissue development, and pathogenesis, and examine the ramifications for re-engineering mammalian physiology. PMID:23561442

  2. Beyond an oncogene, Lin28 is a master regulator of cancer progression.

    Science.gov (United States)

    Wang, Xuefei; Weng, Mingjiao; Jin, Yinji; Yang, Weiwei; Wang, Xin; Wu, Di; Wang, Tianzhen; Li, Xiaobo

    2017-07-26

    The RNA binding protein Lin28 is increased in most human malignancies, and elevated Lin28 is a biomarker for poor prognosis and contributes to cancer progression. Lin28 functions as a master oncogene and is involved in almost all hallmarks of cancer. In this review, we summarize the aberrant molecular expression mechanisms and pathological roles of Lin28 in cancer progression. Moreover, we elaborate on the established molecular mechanisms, from the transcriptional level to the post-transcriptional and translational levels, by which Lin28 regulates cancer progression.

  3. lin28 proteins promote expression of 17∼92 family miRNAs during amphibian development.

    Science.gov (United States)

    Warrander, Fiona; Faas, Laura; Kovalevskiy, Oleg; Peters, Daniel; Coles, Mark; Antson, Alfred A; Genever, Paul; Isaacs, Harry V

    2016-01-01

    Lin28 proteins are post-transcriptional regulators of gene expression with multiple roles in development and the regulation of pluripotency in stem cells. Much attention has focussed on Lin28 proteins as negative regulators of let-7 miRNA biogenesis; a function that is conserved in several animal groups and in multiple processes. However, there is increasing evidence that Lin28 proteins have additional roles, distinct from regulation of let-7 abundance. We have previously demonstrated that lin28 proteins have functions associated with the regulation of early cell lineage specification in Xenopus embryos, independent of a lin28/let-7 regulatory axis. However, the nature of lin28 targets in Xenopus development remains obscure. Here, we show that mir-17∼92 and mir-106∼363 cluster miRNAs are down-regulated in response to lin28 knockdown, and RNAs from these clusters are co-expressed with lin28 genes during germ layer specification. Mature miRNAs derived from pre-mir-363 are most sensitive to lin28 inhibition. We demonstrate that lin28a binds to the terminal loop of pre-mir-363 with an affinity similar to that of let-7, and that this high affinity interaction requires to conserved a GGAG motif. Our data suggest a novel function for amphibian lin28 proteins as positive regulators of mir-17∼92 family miRNAs. © 2015 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc.

  4. Lin28 regulates HER2 and promotes malignancy through multiple mechanisms.

    Science.gov (United States)

    Feng, Chen; Neumeister, Veronique; Ma, Wei; Xu, Jie; Lu, Lingeng; Bordeaux, Jennifer; Maihle, Nita J; Rimm, David L; Huang, Yingqun

    2012-07-01

    The RNA binding protein Lin28 and its paralog Lin28B are associated with advanced human malignancies. Blocking the biogenesis of let-7 miRNA, a tumor suppressor, by Lin28/Lin28B has been thought to underlie their roles in cancer. Here we report that the mRNA for the human epidermal growth factor receptor 2 (HER2), a HER-family receptor tyrosine kinase known to play a critical role in cell proliferation and survival and also a major therapeutic target in breast cancer, is among several targets of Lin28 regulation. We show that Lin28 stimulates HER2 expression at the posttranscriptional level, and that enforced Lin28 expression promotes cancer cell growth via multiple mechanisms. Consistent with its pleiotropic role in regulating gene expression, Lin28 overexpression in primary breast tumors is a powerful predictor of poor prognosis, representing the first report on the impact of Lin28 expression on clinical outcome in human cancer. While revealing another layer of regulation of HER2 expression in addition to gene amplification, our studies also suggest novel mechanistic insights linking Lin28 expression to disease outcome and imply that targeting multiple pathways is a common mechanistic theme of Lin28-mediated regulation in cancer.

  5. The C. elegans LIM homeobox gene lin-11 specifies multiple cell fates during vulval development.

    Science.gov (United States)

    Gupta, Bhagwati P; Wang, Minqin; Sternberg, Paul W

    2003-06-01

    LIM homeobox family members regulate a variety of cell fate choices during animal development. In C. elegans, mutations in the LIM homeobox gene lin-11 have previously been shown to alter the cell division pattern of a subset of the 2 degrees lineage vulval cells. We demonstrate multiple functions of lin-11 during vulval development. We examined the fate of vulval cells in lin-11 mutant animals using five cellular markers and found that lin-11 is necessary for the patterning of both 1 degrees and 2 degrees lineage cells. In the absence of lin-11 function, vulval cells fail to acquire correct identity and inappropriately fuse with each other. The expression pattern of lin-11 reveals dynamic changes during development. Using a temporally controlled overexpression system, we show that lin-11 is initially required in vulval cells for establishing the correct invagination pattern. This process involves asymmetric expression of lin-11 in the 2 degrees lineage cells. Using a conditional RNAi approach, we show that lin-11 regulates vulval morphogenesis. Finally, we show that LDB-1, a NLI/Ldb1/CLIM2 family member, interacts physically with LIN-11, and is necessary for vulval morphogenesis. Together, these findings demonstrate that temporal regulation of lin-11 is crucial for the wild-type vulval patterning.

  6. Lin28 proteins are required for germ layer specification in Xenopus.

    Science.gov (United States)

    Faas, Laura; Warrander, Fiona C; Maguire, Richard; Ramsbottom, Simon A; Quinn, Diana; Genever, Paul; Isaacs, Harry V

    2013-03-01

    Lin28 family proteins share a unique structure, with both zinc knuckle and cold shock RNA-binding domains, and were originally identified as regulators of developmental timing in Caenorhabditis elegans. They have since been implicated as regulators of pluripotency in mammalian stem cells in culture. Using Xenopus tropicalis, we have undertaken the first analysis of the effects on the early development of a vertebrate embryo resulting from global inhibition of the Lin28 family. The Xenopus genome contains two Lin28-related genes, lin28a and lin28b. lin28a is expressed zygotically, whereas lin28b is expressed both zygotically and maternally. Both lin28a and lin28b are expressed in pluripotent cells of the Xenopus embryo and are enriched in cells that respond to mesoderm-inducing signals. The development of axial and paraxial mesoderm is severely abnormal in lin28 knockdown (morphant) embryos. In culture, the ability of pluripotent cells from the embryo to respond to the FGF and activin/nodal-like mesoderm-inducing pathways is compromised following inhibition of lin28 function. Furthermore, there are complex effects on the temporal regulation of, and the responses to, mesoderm-inducing signals in lin28 morphant embryos. We provide evidence that Xenopus lin28 proteins play a key role in choreographing the responses of pluripotent cells in the early embryo to the signals that regulate germ layer specification, and that this early function is probably independent of the recognised role of Lin28 proteins in negatively regulating let-7 miRNA biogenesis.

  7. Lin28a protects against diabetic cardiomyopathy via the PKA/ROCK2 pathway.

    Science.gov (United States)

    Sun, Shuhong; Zhang, Mingming; Lin, Jie; Hu, Jianqiang; Zhang, Rongqing; Li, Congye; Wei, Tianlu; Sun, Dongdong; Wei, Jianqin; Wang, Haichang

    2016-01-01

    Lin28a enhances glucose uptake and insulin-sensitivity. However, the role of Lin28a on experimental diabetic cardiomyopathy (DCM) is not well understood. We investigated the potential role and mechanism ofLin28a in diabetes-induced myocardial dysfunction in mice. Diabetes was induced by intraperitoneal (i.p.) injections of Streptozocin (STZ) in mice. Animals were randomized to be treated with lentivirus carrying Lin28a siRNA or Lin28a cDNA. Cardiac function, cardiomyocyte autophagy, apoptosis and mitochondria morphology in diabetic mice were compared between groups. The target proteins of Lin28a were examined by western blot analysis. Lin28a levels were markedly reduced in the cardiac tissue compared to the control mice. Lin28a overexpression significantly improved left ventricular ejection fraction (LVEF), promoted autophagy, decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice. Lin28a knockdown exacerbated diabetic injury as evidenced by decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pretreatment with a PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide], di-HCl Salt (H89) abolished the beneficial effects of Lin28a overexpression. RhoA-expression and ROCK2-expression were decreased in vivo after Lin28a overexpression, while Lin28a knockdown increased the expression of RhoA and ROCK2 in diabetic mice. Lin28a protects against DCM through PKA/ROCK2 dependent pathway. Lin28a might serve as a potential therapeutic target for the treatment of the patients with DCM. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity.

    Science.gov (United States)

    Kim, Jung Dae; Toda, Chitoku; Ramírez, Cristina M; Fernández-Hernando, Carlos; Diano, Sabrina

    2017-08-01

    The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKI(VMH) ) or downregulate (Lin28aKD(VMH) ) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKI(VMH) or Lin28aKD(VMH) mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKI(VMH) mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKD(VMH) mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKI(VMH) or Lin28aKD(VMH) mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1-dependent role for central Lin28a in glucose homeostasis. © 2017 by the American Diabetes Association.

  9. Detection of lin-4 mRNA in Caenorhabditis elegans Wild Type and Mutants via in Situ Hybridization%原位杂交检测lin-4 mRNA在Caenorhabditis elegans中的表达

    Institute of Scientific and Technical Information of China (English)

    高雅君; 杨玉荣

    2007-01-01

    lin-4是控制Caenorhabditis elegans(C.elegans)幼虫发育的异时性基因,也是一种小RNA分子(microRNA).通过整体原位杂交检测小RNA lin-4在野生型和lin-14、lin-28突变体中的区域性表达,探讨lin-4在C.elegans发育时空控制中的作用.结果表明:lin-4 mRNA在胚胎发育的早期和中期表达,胚胎后期至L1期末没有表达,之后又持续表达,成虫中也可以检测到lin-4 mRNA的存在.在lin-14和lin-28突变体中,lin-4的表达基本与野生型一致,不受lin-14、lin-28基因突变的影响,说明lin-14和lin-28是lin-4的下游基因.

  10. A Dynamic Attitude Measurement System Based on LINS

    Directory of Open Access Journals (Sweden)

    Hanzhou Li

    2014-08-01

    Full Text Available A dynamic attitude measurement system (DAMS is developed based on a laser inertial navigation system (LINS. Three factors of the dynamic attitude measurement error using LINS are analyzed: dynamic error, time synchronization and phase lag. An optimal coning errors compensation algorithm is used to reduce coning errors, and two-axis wobbling verification experiments are presented in the paper. The tests indicate that the attitude accuracy is improved 2-fold by the algorithm. In order to decrease coning errors further, the attitude updating frequency is improved from 200 Hz to 2000 Hz. At the same time, a novel finite impulse response (FIR filter with three notches is designed to filter the dither frequency of the ring laser gyro (RLG. The comparison tests suggest that the new filter is five times more effective than the old one. The paper indicates that phase-frequency characteristics of FIR filter and first-order holder of navigation computer constitute the main sources of phase lag in LINS. A formula to calculate the LINS attitude phase lag is introduced in the paper. The expressions of dynamic attitude errors induced by phase lag are derived. The paper proposes a novel synchronization mechanism that is able to simultaneously solve the problems of dynamic test synchronization and phase compensation. A single-axis turntable and a laser interferometer are applied to verify the synchronization mechanism. The experiments results show that the theoretically calculated values of phase lag and attitude error induced by phase lag can both match perfectly with testing data. The block diagram of DAMS and physical photos are presented in the paper. The final experiments demonstrate that the real-time attitude measurement accuracy of DAMS can reach up to 20″ (1σ and the synchronization error is less than 0.2 ms on the condition of three axes wobbling for 10 min.

  11. Translator and Identity—Taking Lin Yutang as an Example

    Institute of Scientific and Technical Information of China (English)

    任春燕

    2016-01-01

    with the prosperous development of translation, the identity of translator has attracted more and more attention. The relationship of translator and identity is worth studying. This article takes translator Lin Yutang as an example to see how identities influence a translator. The conclusion is that the choice of translation martial, translation strategy, translation attitude and other aspects in translation are influenced by Li Yutang's identities such as his religious identity, class identity, national identity and personal identity.

  12. Nomenclatural Studies Toward a World List of Diptera Genus-Group Names. Part V: Pierre-Justin-Marie Macquart.

    Science.gov (United States)

    Evenhuis, Neal L; Pape, Thomas; Pont, Adrian C

    2016-09-30

    The Diptera genus-group names of Pierre-Justin-Marie Macquart are reviewed and annotated. A total of 399 available genus-group names in 69 families of Diptera are listed alphabetically, for each name giving author, year and page of original publication, originally included species, type species and method of fixation, current status of the name, family placement, and a list of any emendations of it that have been found in the literature. Remarks are given to clarify nomenclatural or taxonomic information. In addition, an index to all the species-group names of Diptera proposed by Macquart (3,611, of which 3,543 are available) is given with bibliographic reference (year and page) to each original citation.        The following type species are designated herein: Agculocera nigra Macquart, 1855 for Onuxicera Macquart, 1855, present designation [Tachinidae]; Trixa imhoffi Macquart, 1834, for Semiomyia Macquart, 1848, present designation [Tachinidae].        The following type species are designated herein with fixation under ICZN Code Art. 70.3.2: Azelia nebulosa Robineau-Desvoidy, 1830 for Atomogaster Macquart, 1835, present designation [Muscidae]; Tachydromia vocatoria Fallén, 1816 for Chelipoda Macquart, 1835, present designation [Empididae]; Eriocera macquarti Enderlein, 1912 for Eriocera Macquart, 1838, present designation [Limoniidae]; Limosina acutangula Zetterstedt, 1847 for Heteroptera Macquart, 1835, present designation [Sphaeroceridae]; Phryxe pavoniae Robineau-Desvoidy, 1830 for Masicera Macquart, 1834, present designation [Tachinidae]; Pachymyia macquartii Townsend, 1916 for Pachymyia Macquart, 1844, present designation [Tachinidae].        Earlier valid subsequent type-species designations have been found in this study for the following: Anisophysa Macquart, 1835 [Sepsidae]; Diphysa Macquart, 1838 [Stratiomyidae]; Pachyrhina Macquart, 1834 [Tipulidae]; Silbomyia Macquart, 1844 [Calliphoridae].        One name is raised from

  13. Analisis Kebutuhan Bandwidth Pada Pemanfaatan Web Streaming Justin.tv Sebagai Media E-Learning Dengan Menggunakan Wirecast Dan Desktop Presenter

    Directory of Open Access Journals (Sweden)

    Muhammad Ubaidilah

    2014-05-01

    Full Text Available Perkembangan teknologi informasi begitu cepat seperti sekarang telah banyak mengubah sudut pandang banyak orang, antara lain sudut pandang orang untuk mengubah dunia pendidikan menjadi lebih baik. Salah satu contohnya pembelajaran berbasis Information and Communication Technologies (ICT yaitu pembelajaran menggunakan video streaming. Dengan instalasi software open source Wirecast dan Desktop presenter digunakan untuk membuat video pembelajaran Streaming, disiarkan secara real time melalui media broadcast justin.tv (internet TV Channel, diharapkan dapat lebih mendukung konsep pembelajaran kapan dan dimana saja. Masalah terbesar dari teknologi ini adalah keterbatasan bandwidth. Bandwidth adalah parameter penting untuk melakukan streaming dalam jaringan. Sedangkan proses komunikasi menggunakan video digital ini menghabiskan resource yang cukup besar. Sehingga penggunaan wireshark di sini sangat diperlukan untuk menganalisis bandwidth pada paket yang diterima oleh client. Dari hasil pengukuran video dengan standar H.264 resolusi (720 x 540, dengan rata-rata 20 menit dalam pengambilan sampel, sebanyak 30 pengujian sampel streaming video menggunakan wireshark, diperoleh rata-rata throughput keseluruhan 0,343 Mbps, rata-rata throughput terendah 0,309 Mbps dan throughput tertinggi 0,372 Mbps. Dapat disimpulkan bahwa jika dihasilkan throughput yang lebih besar maka kualitas video streaming akan lebih baik, tetapi jika throughput dihasilkan semakin kecil maka kualitas video streaming akan menurun

  14. Role of LIN28A in mouse and human trophoblast cell differentiation.

    Science.gov (United States)

    Seabrook, Jill L; Cantlon, Jeremy D; Cooney, Austin J; McWhorter, Erin E; Fromme, Brittany A; Bouma, Gerrit J; Anthony, Russell V; Winger, Quinton A

    2013-10-01

    Proper regulation of trophoblast proliferation, differentiation, and function are critical for placenta development and function. The RNA-binding protein, LIN28A, has been well characterized as a potent regulator of differentiation in embryonic stem cells; however, little is known about the function of LIN28A in the placenta. We assessed LIN28A in vitro using mouse trophoblast stem (mTS) cells and human trophoblast cells (ACH-3P). We observed that LIN28A decreased and let-7 miRNA increased when mTS cells were induced to differentiate into mouse trophoblast giant cells (mTGCs) upon the removal of FGF4, heparin and conditioned medium. Similarly, we observed that LIN28A decreased in ACH-3P cells induced to syncytialize with forskolin treatment. To assess LIN28A in vivo we examined Embryonic Day 11.5 mouse placenta and observed abundant LIN28A in the chorioallantoic interface and labyrinth layer, with little LIN28A staining in spongiotrophoblast or differentiated mTGCs. Additionally, shRNA-mediated LIN28A knockdown in ACH-3P cells resulted in increased spontaneous syncytialization, and increased levels of syncytiotrophoblast markers hCG, LGALS13, and ERVW-1 mRNA. Additionally, targeted degradation of LIN28A mRNA increased responsiveness to forskolin-induced differentiation. In contrast, targeted degradation of Lin28a mRNA in mTS cells did not alter cell phenotype when maintained under proliferative culture conditions. Together, these data establish that LIN28A has a functional role in regulating trophoblast differentiation and function, and that loss of LIN28A in human trophoblast is sufficient to induce differentiation, but does not induce differentiation in the mouse.

  15. Role of LIN28A in Mouse and Human Trophoblast Cell Differentiation1

    Science.gov (United States)

    Seabrook, Jill L.; Cantlon, Jeremy D.; Cooney, Austin J.; McWhorter, Erin E.; Fromme, Brittany A.; Bouma, Gerrit J.; Anthony, Russell V.; Winger, Quinton A.

    2013-01-01

    ABSTRACT Proper regulation of trophoblast proliferation, differentiation, and function are critical for placenta development and function. The RNA-binding protein, LIN28A, has been well characterized as a potent regulator of differentiation in embryonic stem cells; however, little is known about the function of LIN28A in the placenta. We assessed LIN28A in vitro using mouse trophoblast stem (mTS) cells and human trophoblast cells (ACH-3P). We observed that LIN28A decreased and let-7 miRNA increased when mTS cells were induced to differentiate into mouse trophoblast giant cells (mTGCs) upon the removal of FGF4, heparin and conditioned medium. Similarly, we observed that LIN28A decreased in ACH-3P cells induced to syncytialize with forskolin treatment. To assess LIN28A in vivo we examined Embryonic Day 11.5 mouse placenta and observed abundant LIN28A in the chorioallantoic interface and labyrinth layer, with little LIN28A staining in spongiotrophoblast or differentiated mTGCs. Additionally, shRNA-mediated LIN28A knockdown in ACH-3P cells resulted in increased spontaneous syncytialization, and increased levels of syncytiotrophoblast markers hCG, LGALS13, and ERVW-1 mRNA. Additionally, targeted degradation of LIN28A mRNA increased responsiveness to forskolin-induced differentiation. In contrast, targeted degradation of Lin28a mRNA in mTS cells did not alter cell phenotype when maintained under proliferative culture conditions. Together, these data establish that LIN28A has a functional role in regulating trophoblast differentiation and function, and that loss of LIN28A in human trophoblast is sufficient to induce differentiation, but does not induce differentiation in the mouse. PMID:24006280

  16. High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer.

    Science.gov (United States)

    Hamano, R; Miyata, H; Yamasaki, M; Sugimura, K; Tanaka, K; Kurokawa, Y; Nakajima, K; Takiguchi, S; Fujiwara, Y; Mori, M; Doki, Y

    2012-04-10

    Lin28 is a negative regulator of the tumour suppressor microRNA, let-7, suggesting its role in tumourigenesis. However, the clinical significance of Lin28 expression in oesophageal cancer has not been elucidated. Lin28 and Lin28B expression was examined by immunohistochemistry in 161 tissues from patients with oesophageal cancer who had undergone curative surgery. The relationship between the expressions of Lin28 and Lin28B and various clinicopathological factors was examined. In vitro assays were conducted to determine the role of Lin28 in aggressiveness of oesophageal cancers using oesophageal cancer cell line. Lin28 and Lin28B were overexpressed in oesophageal cancer cells compared with non-cancerous epithelial cells, especially in the invasive front. High expression of Lin28 and Lin28B correlated significantly with lymph node metastasis and poor prognosis. High expression of Lin28B expression correlated significantly with low expression of let-7. Multivariate analysis also identified Lin28B expression as an independent prognostic factor. In vitro assays showed that the proliferative and invasive activities were significantly reduced in Lin28B-knockdown cells, compared with control cells. High expression of Lin28 is associated with poor prognosis and high tumour aggressiveness in oesophageal cancer and these effects are mediated through increased proliferation and invasiveness of oesophageal cancer cells.

  17. Lin28a is dormant, functional, and dispensable during mouse oocyte-to-embryo transition.

    Science.gov (United States)

    Flemr, Matyas; Moravec, Martin; Libova, Veronika; Sedlacek, Radislav; Svoboda, Petr

    2014-06-01

    The oocyte-to-embryo transition (OET) denotes transformation of a highly differentiated oocyte into totipotent blastomeres of the early mammalian embryo. OET depends exclusively on maternal RNAs and proteins accumulated during oocyte growth, which implies importance of post-transcriptional control of gene expression. OET includes replacement of abundant maternal microRNAs (miRNAs), enriched also in differentiated cells and exemplified by the Let-7 family, with embryonic miRNAs common in pluripotent stem cells (the miR-290 family in the mouse). Lin28a and its homolog Lin28b encode RNA-binding proteins, which interfere with Let-7 maturation and facilitate reprogramming of induced pluripotent stem cells. Both Lin28a and Lin28b transcripts are abundant in mouse oocytes. To test the role of maternal expression of Lin28a and Lin28b during oocyte-to-zygote reprogramming, we generated mice with oocyte-specific knockdown of both genes by using transgenic RNA interference. Lin28a and Lin28b are dispensable during oocyte growth because their knockdown has no effect on Let-7a levels in fully grown germinal vesicle (GV)-intact oocytes. Furthermore, transgenic females were fertile and produced healthy offspring, and their overall breeding performance was comparable to that of wild-type mice. At the same time, 2-cell embryos derived from transgenic females showed up-regulation of mature Let-7, suggesting that maternally provided LIN28A and LIN28B function during zygotic genome activation. Consistent with this conclusion is increased translation of Lin28a transcripts upon resumption of meiosis. Our data imply dual repression of Let-7 during OET in the mouse model, the selective suppression of Let-7 biogenesis by Lin28 homologs superimposed on previously reported global suppression of miRNA activity. © 2014 by the Society for the Study of Reproduction, Inc.

  18. Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer.

    Science.gov (United States)

    Faria, André M; Sbiera, Silviu; Ribeiro, Tamaya C; Soares, Iberê C; Mariani, Beatriz M P; Freire, Daniel S; de Sousa, Gabriela R V; Lerario, Antônio M; Ronchi, Cristina L; Deutschbein, Timo; Wakamatsu, Alda; Alves, Venancio A F; Zerbini, Maria Claudia N; Mendonca, Berenice B; Fragoso, Maria Candida B V; Latronico, Ana Claudia; Fassnacht, Martin; Almeida, Madson Q

    2015-04-01

    LIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P = 0·01), but for overall survival only a trend was detectable (P = 0·117). In the multivariate analysis, only Ki67 index ≥10% (HR 4·6, P = 0·000) and weak LIN28 protein expression (HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011] and was highly associated with reduced overall (P = 0·01) and disease-free survival (P = 0·01). However, mir-9 prognostic role should be further evaluated in a larger cohort. Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome. © 2014 John Wiley & Sons Ltd.

  19. Lin28 promotes growth of prostate cancer cells and activates the androgen receptor.

    Science.gov (United States)

    Tummala, Ramakumar; Nadiminty, Nagalakshmi; Lou, Wei; Zhu, Yezi; Gandour-Edwards, Regina; Chen, Hong-Wu; Evans, Christopher P; Gao, Allen C

    2013-07-01

    Prostate cancer (CaP) progresses to a castration-resistant state assisted by multifold molecular changes, most of which involve activation of the androgen receptor (AR). Having previously demonstrated the importance of the Lin28/let-7/Myc axis in CaP, we tested the hypothesis that Lin28 is overexpressed in CaP and that it activates AR and promotes growth of CaP cells. We analyzed human clinical CaP samples for the expression of Lin28 by quantitative real-time RT-PCR, Western blot analysis, and IHC. Growth characteristics of CaP cell lines transiently and stably expressing Lin28 were examined. The clonogenic ability of CaP cells expressing Lin28 was determined by colony formation and soft agar assays. Increase in expression of AR and subsequent increase in transcription of AR-target genes were analyzed by quantitative real-time RT-PCR, luciferase assays, and ELISA. LNCaP cells stably expressing Lin28 were injected into nude mice, and tumorigenesis was monitored. We found that Lin28 is overexpressed in clinical CaP compared to benign prostates. Overexpression of Lin28 enhanced, while down-regulation reduced, growth of CaP cells. Lin28 enhanced the ability of CaP cells to form colonies in anchorage-dependent and anchorage-independent conditions. LNCaP cells stably expressing Lin28 exhibited significantly higher tumorigenic ability in vivo. Lin28 induced expression of the AR and its target genes such as PSA and NKX3.1. Collectively, our findings demonstrate a novel role for Lin28 in CaP development and activation of the AR axis. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  20. lin-28 controls the succession of cell fate choices via two distinct activities.

    Directory of Open Access Journals (Sweden)

    Bhaskar Vadla

    Full Text Available lin-28 is a conserved regulator of cell fate succession in animals. In Caenorhabditis elegans, it is a component of the heterochronic gene pathway that governs larval developmental timing, while its vertebrate homologs promote pluripotency and control differentiation in diverse tissues. The RNA binding protein encoded by lin-28 can directly inhibit let-7 microRNA processing by a novel mechanism that is conserved from worms to humans. We found that C. elegans LIN-28 protein can interact with four distinct let-7 family pre-microRNAs, but in vivo inhibits the premature accumulation of only let-7. Surprisingly, however, lin-28 does not require let-7 or its relatives for its characteristic promotion of second larval stage cell fates. In other words, we find that the premature accumulation of mature let-7 does not account for lin-28's precocious phenotype. To explain let-7's role in lin-28 activity, we provide evidence that lin-28 acts in two steps: first, the let-7-independent positive regulation of hbl-1 through its 3'UTR to control L2 stage-specific cell fates; and second, a let-7-dependent step that controls subsequent fates via repression of lin-41. Our evidence also indicates that let-7 functions one stage earlier in C. elegans development than previously thought. Importantly, lin-28's two-step mechanism resembles that of the heterochronic gene lin-14, and the overlap of their activities suggests a clockwork mechanism for developmental timing. Furthermore, this model explains the previous observation that mammalian Lin28 has two genetically separable activities. Thus, lin-28's two-step mechanism may be an essential feature of its evolutionarily conserved role in cell fate succession.

  1. Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer

    Science.gov (United States)

    2015-09-01

    AWARD NUMBER: W81XWH-14-1-0138 TITLE: Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer PRINCIPAL INVESTIGATOR: John P. Hagan...2015 4. TITLE AND SUBTITLE Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1...prognosis in multiple cancer types, including ovarian. Silent in almost all adult cells, the Lin28/let-7 pathway is implicated directly in cancer stem

  2. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.

    Science.gov (United States)

    Nguyen, Liem H; Robinton, Daisy A; Seligson, Marc T; Wu, Linwei; Li, Lin; Rakheja, Dinesh; Comerford, Sarah A; Ramezani, Saleh; Sun, Xiankai; Parikh, Monisha S; Yang, Erin H; Powers, John T; Shinoda, Gen; Shah, Samar P; Hammer, Robert E; Daley, George Q; Zhu, Hao

    2014-08-11

    Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extended latency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletion reduced tumor burden and prolonged survival. Igf2bp proteins are upregulated, and Igf2bp3 is required in the context of LIN28B overexpression to promote growth. Therefore, multiple murine models demonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans.

    Science.gov (United States)

    Tu, Ho-Chou; Schwitalla, Sarah; Qian, Zhirong; LaPier, Grace S; Yermalovich, Alena; Ku, Yuan-Chieh; Chen, Shann-Ching; Viswanathan, Srinivas R; Zhu, Hao; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A; Morikawa, Teppei; Mima, Kosuke; Sukawa, Yasutaka; Yang, Juhong; Meredith, Gavin; Fuchs, Charles S; Ogino, Shuji; Daley, George Q

    2015-05-15

    Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc(Min/+) mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target. © 2015 Tu et al.; Published by Cold Spring Harbor Laboratory Press.

  4. Lin28A and androgen receptor expression in ER-/Her2+ breast cancer.

    Science.gov (United States)

    Shen, Honghong; Yang, Yong; Zhao, Lin; Yuan, Jinyang; Niu, Yun

    2016-02-01

    The aim of this study was to examine the expression of Lin28A and androgen receptor (AR) in ER-/Her2+ breast cancer, and to research the association of Lin28A and AR co-expression status with patients' prognosis. The expression of Lin28A and AR in formalin-fixed and paraffin-embedded surgical sections from 305 patients with ER-/Her2+ breast cancer was analyzed by immunohistochemistry, and the co-expression patterns in breast cancer cells were investigated by immunofluorescent staining. The impact of the expression of Lin28A and AR in prognosis was also assessed by the Kaplan-Meier, univariate, and multivariate logistic regression models. This study included 305 cases ER-/Her2+ breast cancer patients. Lin28A and AR were expressed in 240 cases (78.7 %) and 220 cases (72.1 %), respectively. Lin28A tended to be higher in AR-positive patients (75.0 %). Lin28A and AR co-expression (Lin28+/AR+) was significantly associated with high tumor grade (G3) (p = 0.023) and high Ki67 index (p = 0.020). The mRNA and protein expression levels of Lin28A and AR were higher in MDA-MB-453 cells (ER-/Her2+) than in the MDA-MB-231 cells (ER-/Her2-). In univariate analysis, Lin28A+/AR+ was significant risk factors associated with unfavorable OS (p = 0.049) and RFS (p = 0.019). Kaplan-Meier analysis showed that Lin28A+/AR+ expression showed lower RFS rates compared with Lin28A-/AR+ (p = 0.043) and Lin28A-/AR- patients(p = 0.019). Multivariate cox model showed that Lin28A+/AR+ remained an independent negative prognostic factor for RFS. Our study showed that Lin28A and AR co-expressed in ER-/Her-2+ breast cancer and correlated with poor prognosis. The possibility that Lin28A may drive AR expression via a positive feedback mechanism remains to be tested.

  5. A Rapid Induction Mechanism for Lin28a in Trophic Responses.

    Science.gov (United States)

    Amen, Alexandra M; Ruiz-Garzon, Claudia R; Shi, Jay; Subramanian, Megha; Pham, Daniel L; Meffert, Mollie K

    2017-02-02

    Environmental cues provoke rapid transitions in gene expression to support growth and cellular plasticity through incompletely understood mechanisms. Lin28 RNA-binding proteins have evolutionarily conserved roles in post-transcriptional coordination of pro-growth gene expression, but signaling pathways allowing trophic stimuli to induce Lin28 have remained uncharacterized. We find that Lin28a protein exhibits rapid basal turnover in neurons and that mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the RNA-silencing factor HIV TAR-RNA-binding protein (TRBP) promotes binding and stabilization of Lin28a, but not Lin28b, with an accompanying reduction in Lin28-regulated miRNAs, downstream of brain-derived neurotrophic factor (BDNF). Binding of Lin28a to TRBP in vitro is also enhanced by phospho-mimic TRBP. Further, phospho-TRBP recapitulates BDNF-induced neuronal dendritic spine growth in a Lin28a-dependent manner. Finally, we demonstrate MAPK-dependent TRBP and Lin28a induction, with physiological function in growth and survival, downstream of diverse growth factors in multiple primary cell types, supporting a broad role for this pathway in trophic responses. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Positive expression of Lin28 is correlated with poor survival in gastric carcinoma.

    Science.gov (United States)

    Xu, Chaoyang; Shen, Jiangguo; Xie, Shuduo; Jiang, Zhinong; Huang, Liming; Wang, Linbo

    2013-03-01

    The purpose of this study was to investigate the expression of Lin28 in gastric carcinoma and to assess its clinical significance. The expression level of Lin28 was assessed by reverse-transcriptase polymerase chain reaction in 10 surgically resected gastric carcinoma and corresponding normal tissues, and by immunohistochemical staining in surgically resected gastric carcinoma tissues of 229 patients, including 215 curative resection patients and 14 palliative resection patients. The expression level of Lin28 mRNA in gastric carcinoma tissues and corresponding normal tissues had no statistically significant difference. In curative resection patients, Lin28 protein expression was positive in 99 of 215 (46.0 %) gastric carcinoma tissues. In palliative resection patients, Lin28 protein expression was positive in 4 of 14 (28.6 %) gastric carcinoma tissues. In R0 patients, Lin28 protein positive expression was correlated with poor outcome (P = 0.017). In multivariate analysis, the Lin28 protein positive expression was a significant independent prognostic factor for overall survival (P = 0.024; HR, 1,768; 95 % CI 1.077-2.903). Our results indicate that Lin28 was expressed in both gastric carcinoma and corresponding normal tissues. Lin28 protein positive expression served as an independent prognostic factor.

  7. LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance.

    Science.gov (United States)

    Wilbert, Melissa L; Huelga, Stephanie C; Kapeli, Katannya; Stark, Thomas J; Liang, Tiffany Y; Chen, Stella X; Yan, Bernice Y; Nathanson, Jason L; Hutt, Kasey R; Lovci, Michael T; Kazan, Hilal; Vu, Anthony Q; Massirer, Katlin B; Morris, Quaid; Hoon, Shawn; Yeo, Gene W

    2012-10-26

    LIN28 is a conserved RNA-binding protein implicated in pluripotency, reprogramming, and oncogenesis. It was previously shown to act primarily by blocking let-7 microRNA (miRNA) biogenesis, but here we elucidate distinct roles of LIN28 regulation via its direct messenger RNA (mRNA) targets. Through crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells and somatic cells expressing exogenous LIN28, we have defined discrete LIN28-binding sites in a quarter of human transcripts. These sites revealed that LIN28 binds to GGAGA sequences enriched within loop structures in mRNAs, reminiscent of its interaction with let-7 miRNA precursors. Among LIN28 mRNA targets, we found evidence for LIN28 autoregulation and also direct but differing effects on the protein abundance of splicing regulators in somatic and pluripotent stem cells. Splicing-sensitive microarrays demonstrated that exogenous LIN28 expression causes widespread downstream alternative splicing changes. These findings identify important regulatory functions of LIN28 via direct mRNA interactions. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Reversible acetylation of Lin28 mediated by PCAF and SIRT1.

    Science.gov (United States)

    Wang, Ling-xia; Wang, Jing; Qu, Ting-ting; Zhang, Ye; Shen, Yu-fei

    2014-06-01

    Lin28 is a small RNA-binding protein that plays an important role in regulating developmental timing, stem cell reprogramming, and oncogenesis. However, the significance of the effect of post-translational modifications on Lin28 activity is not fully understood. In this study, we demonstrated that PCAF directly interacted with and acetylated Lin28. We also showed that the acetylation of Lin28 can be specifically reversed by the deacetylase SIRT1. These findings suggest that the PCAF/SIRT1 balance plays an important role in regulating Lin28 activity. Furthermore, we found that the cold shock domain of Lin28 is the major target of PCAF-mediated acetylation, which leads to a severe reduction in the Lin28 protein levels and an increase in the level of mature let-7a. This study provides the first demonstration that post-translational modification regulates Lin28 activity during let-7a biogenesis and sheds light on the regulation of Lin28 in ES cells and carcinogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Oncogenic mechanisms of Lin28 in breast cancer: new functions and therapeutic opportunities.

    Science.gov (United States)

    Xiong, Hanchu; Zhao, Wenhe; Wang, Ji; Seifer, Benjamin J; Ye, Chenyang; Chen, Yongxia; Jia, Yunlu; Chen, Cong; Shen, Jianguo; Wang, Linbo; Sui, Xinbing; Zhou, Jichun

    2017-04-11

    The RNA binding protein Lin28 is best known for the critical role in cell development, recent researches also have implied its oncogenic function in various human cancers, including breast cancer. Specifically, aberrant Lin28 participates in multiple pathological processes, such as proliferation, metastasis, radiotherapy and chemotherapy resistance, metabolism, immunity and inflammation as well as stemness. In this review, we summarize the let-7-dependent and let-7-independent mechanism regulated by Lin28, focusing on its relation with tumor hallmarks in breast cancer, and subsequently discuss our present knowledge of Lin28 to develop a molecular-based therapeutic strategy against breast cancer.

  10. Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma.

    Science.gov (United States)

    Lozier, Ann M; Rich, Maria E; Grawe, Anissa Pedersen; Peck, Anderson S; Zhao, Ping; Chang, Anthony Ting-Tung; Bond, Jeffrey P; Sholler, Giselle Saulnier

    2015-01-01

    LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.

  11. The C. elegans Chp/Wrch Ortholog CHW-1 Contributes to LIN-18/Ryk and LIN-17/Frizzled Signaling in Cell Polarity.

    Science.gov (United States)

    Kidd, Ambrose R; Muñiz-Medina, Vanessa; Der, Channing J; Cox, Adrienne D; Reiner, David J

    2015-01-01

    Wnt signaling controls various aspects of developmental and cell biology, as well as contributing to certain cancers. Expression of the human Rho family small GTPase Wrch/RhoU is regulated by Wnt signaling, and Wrch and its paralog Chp/RhoV are both implicated in oncogenic transformation and regulation of cytoskeletal dynamics. We performed developmental genetic analysis of the single Caenorhabditis elegans ortholog of Chp and Wrch, CHW-1. Using a transgenic assay of the distal tip cell migration, we found that wild-type CHW-1 is likely to be partially constitutively active and that we can alter ectopic CHW-1-dependent migration phenotypes with mutations predicted to increase or decrease intrinsic GTP hydrolysis rate. The vulval P7.p polarity decision balances multiple antagonistic Wnt signals, and also uses different types of Wnt signaling. Previously described cooperative Wnt receptors LIN-17/Frizzled and LIN-18/Ryk orient P7.p posteriorly, with LIN-17/Fz contributing approximately two-thirds of polarizing activity. CHW-1 deletion appears to equalize the contributions of these two receptors. We hypothesize that CHW-1 increases LIN-17/Fz activity at the expense of LIN-18/Ryk, thus making the contribution of these signals unequal. For P7.p to polarize correctly and form a proper vulva, LIN-17/Fz and LIN-18/Ryk antagonize other Wnt transmembrane systems VANG-1/VanGogh and CAM-1/Ror. Our genetic data suggest that LIN-17/Fz represses both VANG-1/VanGogh and CAM-1/Ror, while LIN-18/Ryk represses only VANG-1. These data expand our knowledge of a sophisticated signaling network to control P7.p polarity, and suggests that CHW-1 can alter ligand gradients or receptor priorities in the system.

  12. Brecht e Ivan Lins: Um diálogo intertextual

    Directory of Open Access Journals (Sweden)

    Eloá Heise

    2000-11-01

    Full Text Available Das Thema dieses Aufsatzes betrifft die Verbindungen und Wechselwirkungen zwischen Dichtern und ihren Werken über sprachliche und politische Grenzen hinweg. Am Beispiel von Brechts Gedicht An die Nachgeborenen (1938 und des Songs Aos nossos filhos (An unsere Kinder - Ende der 70er Jahre von Ivan Lins und Vitor Martins wird gezeigt, daß die Interpretation nicht auf eine immanente Perspektive beschränkt werden kann. Um eine angemessene Analyse geben zu können, ist es notwendig, den historischen und sozio-politischen Kontext in Betracht zu ziehen.

  13. Selective blockade of microRNA processing by Lin-28

    OpenAIRE

    Viswanathan, Srinivas R.; Daley, George Q.; Gregory, Richard I.

    2008-01-01

    MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked post-transcriptionally in embryonic stem (ES) cells, embryonal carcinoma (EC) cells, and primary tumors. Here we show that Lin-28, a developmentally regulated RNA-binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Usi...

  14. Lin28B and Let-7 in the Control of Sympathetic Neurogenesis and Neuroblastoma Development.

    Science.gov (United States)

    Hennchen, Melanie; Stubbusch, Jutta; Abarchan-El Makhfi, Ikram; Kramer, Marco; Deller, Thomas; Pierre-Eugene, Cécile; Janoueix-Lerosey, Isabelle; Delattre, Olivier; Ernsberger, Uwe; Schulte, Johannes B; Rohrer, Hermann

    2015-12-16

    The RNA binding protein Lin28B is expressed in developing tissues and sustains stem and progenitor cell identity as a negative regulator of the Let-7 family of microRNAs, which induces differentiation. Lin28B is activated in neuroblastoma (NB), a childhood tumor in sympathetic ganglia and adrenal medulla. Forced expression of Lin28B in embryonic mouse sympathoadrenal neuroblasts elicits postnatal NB formation. However, the normal function of Lin28B in the development of sympathetic neurons and chromaffin cells and the mechanisms involved in Lin28B-induced tumor formation are unclear. Here, we demonstrate a mirror-image expression of Lin28B and Let-7a in developing chick sympathetic ganglia. Lin28B expression is not restricted to undifferentiated progenitor cells but, is observed in proliferating noradrenergic neuroblasts. Lin28 knockdown in cultured sympathetic neuroblasts decreases proliferation, whereas Let-7 inhibition increases the proportion of neuroblasts in the cell cycle. Lin28B overexpression enhances proliferation, but only during a short developmental period, and it does not reduce Let-7a. Effects of in vivo Lin28B overexpression were analyzed in the LSL-Lin28B(DBHiCre) mouse line. Sympathetic ganglion and adrenal medulla volume and the expression level of Let-7a were not altered, although Lin28B expression increased by 12- to 17-fold. In contrast, Let-7a expression was strongly reduced in LSL-Lin28B(DbhiCre) NB tumor tissue. These data demonstrate essential functions for endogenous Lin28 and Let-7 in neuroblast proliferation. However, Lin28B overexpression neither sustains neuroblast proliferation nor affects let-7 expression. Thus, in contrast to other pediatric tumors, Lin28B-induced NB is not due to expansion of proliferating embryonic neuroblasts, and Let-7-independent functions are implicated during initial NB development. Lin28A/B proteins are highly expressed in early development and maintain progenitor cells by blocking the biogenesis and

  15. Fetal deficiency of lin28 programs life-long aberrations in growth and glucose metabolism.

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    Shinoda, Gen; Shyh-Chang, Ng; Soysa, T Yvanka de; Zhu, Hao; Seligson, Marc T; Shah, Samar P; Abo-Sido, Nora; Yabuuchi, Akiko; Hagan, John P; Gregory, Richard I; Asara, John M; Cantley, Lewis C; Moss, Eric G; Daley, George Q

    2013-08-01

    LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of Lin28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of Lin28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal Lin28b acts at least in part via mTORC1 signaling.

  16. Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1.

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    Ma, Xiaoyu; Li, Chenchen; Sun, Linchong; Huang, De; Li, Tingting; He, Xiaoping; Wu, Gongwei; Yang, Zheng; Zhong, Xiuying; Song, Libing; Gao, Ping; Zhang, Huafeng

    2014-10-10

    Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia- or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A- and Lin28B-mediated cancer proliferation both in vitro and in vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7.

  17. Blurred Boundaries: The RNA Binding Protein Lin28A Is Also an Epigenetic Regulator.

    Science.gov (United States)

    Tan, Frederick E; Yeo, Gene W

    2016-01-07

    Lin28A is best known as a post-transcriptional regulator of gene expression. In this issue, Zeng et al. (2016) show that Lin28A has an unexpected role as an epigenetic regulator of DNA. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Clinicopathological Characteristics of Patients with Gastric Cancer according to the Expression of LIN28A.

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    Park, Chan Hyuk; Lee, Jung Hwa; Lee, Na Keum; Lee, Yong Chan; Lee, Sang Kil

    2016-09-15

    Although LIN28A is known to potentially play a role in the oncogenesis of various cancers, whether LIN28A expression is a predictor of poor prognosis in patients with gastric cancer has not been fully explored. We sought to evaluate clinicopathological characteristics according to the expression of LIN28A in numerous gastric cancer tissue samples. LIN28A expression was evaluated by immunohistochemical (IHC) analysis of a tissue microarray comprising 288 gastric cancer tissues and 288 adjacent normal tissues. Clinicopathological characteristics, including overall survival, were compared according to LIN28A expression. The IHC staining score was lower for the cancer tissues than the normal tissues (pLIN28A expression groups. In addition, the 5-year overall survival rate did not differ between the two groups: 75.3% (95% confidence interval [CI], 69.3% to 81.7%) versus 71.6% (95% CI, 63.3% to 80.9%) for low versus high expression, respectively. The expression of LIN28A did not appear to play a distinct role in predicting the clinicopathological characteristics of patients with gastric cancer. In addition, LIN28A expression was not an independently associated factor for overall survival in patients with gastric cancer.

  19. Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

    Science.gov (United States)

    Zeng, Yaxue; Yao, Bing; Shin, Jaehoon; Lin, Li; Kim, Namshik; Song, Qifeng; Liu, Shuang; Su, Yijing; Guo, Junjie U; Huang, Luoxiu; Wan, Jun; Wu, Hao; Qian, Jiang; Cheng, Xiaodong; Zhu, Heng; Ming, Guo-li; Jin, Peng; Song, Hongjun

    2016-01-07

    Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal enrichment of Lin28A binding around transcription start sites and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and have implications for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. RNA-binding protein LIN28 is a sensitive marker of ovarian primitive germ cell tumours.

    Science.gov (United States)

    Xue, Debin; Peng, Yan; Wang, Fenghua; Allan, Robert W; Cao, Dengfeng

    2011-09-01

    LIN28 is an RNA-binding protein that has been detected in testicular germ cell tumours (GCTs), but its status in ovarian GCTs is unknown. The aim was to determine the immunohistochemical profile of LIN28 in ovarian GCTs. Immunohistochemistry of LIN28 was performed in 110 primary and 11 metastatic ovarian GCTs. The percentage of tumour cells stained was scored as 0, 1+ (1-30% cells), 2+ (31-60%), 3+ (61-90%), and 4+ (>90%). To determine its specificity, we stained LIN28 in 119 non-GCTs, including 37 clear cell carcinomas. Strong 4+ LIN28 staining was seen in 4/4 (100%) gonadoblastomas, 7/7 (100%) embryonal carcinomas (ECs), and 41/41 (100%) yolk sac tumours (YSTs). Among 39 dysgerminomas, 4+ staining was seen in 37 and 3+ staining in two (strong in 37; mixed weak and strong in two). Twelve of 14 immature teratomas showed variable LIN28 staining (1+ to 4+) in the immature neuroepithelium (weak to strong staining), whereas mature teratomas, carcinoids, struma ovarii and strumal carcinoids were negative. Only 5/117 non-GCTs (1/37 clear cell carcinomas) showed weak to moderate 1-2+ staining. LIN28 is a sensitive marker for gonadoblastomas, dysgerminomas, ECs, and YSTs. LIN28 can be used to distinguish them from non-GCTs. © 2011 Blackwell Publishing Limited.

  1. Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes.

    Science.gov (United States)

    Jin, Jianyu; Jing, Wei; Lei, Xin-Xiang; Feng, Chen; Peng, Shuping; Boris-Lawrie, Kathleen; Huang, Yingqun

    2011-05-01

    The stem cell protein Lin28 functions to inhibit the biogenesis of a group of miRNAs but also stimulates the expression of a subset of mRNAs at the post-transcriptional level, the underlying mechanism of which is not yet understood. Here we report the characterization of the molecular interplay between Lin28 and RNA helicase A (RHA) known to play an important role in remodeling ribonucleoprotein particles during translation. We show that reducing Lin28 expression results in decreased RHA association with polysomes while increasing Lin28 expression leads to elevated RHA association. Further, the carboxyl terminus of Lin28 is necessary for interaction with both the amino and carboxyl termini of RHA. Importantly, a carboxyl terminal deletion mutant of Lin28 that retains RNA-binding activity fails to interact with RHA and exhibits dominant-negative effects on Lin28-dependent stimulation of translation. Taken together, these results lead us to suggest that Lin28 may stimulate translation by actively recruiting RHA to polysomes. © The Author(s) 2011. Published by Oxford University Press.

  2. Importance of the pluripotency factor LIN28 in the mammalian nucleolus during early embryonic development.

    Science.gov (United States)

    Vogt, Edgar J; Meglicki, Maciej; Hartung, Kristina Ilka; Borsuk, Ewa; Behr, Rüdiger

    2012-12-01

    The maternal nucleolus is required for proper activation of the embryonic genome (EGA) and early embryonic development. Nucleologenesis is characterized by the transformation of a nucleolar precursor body (NPB) to a mature nucleolus during preimplantation development. However, the function of NPBs and the involved molecular factors are unknown. We uncover a novel role for the pluripotency factor LIN28, the biological significance of which was previously demonstrated in the reprogramming of human somatic cells to induced pluripotent stem (iPS) cells. Here, we show that LIN28 accumulates at the NPB and the mature nucleolus in mouse preimplantation embryos and embryonic stem cells (ESCs), where it colocalizes with the nucleolar marker B23 (nucleophosmin 1). LIN28 has nucleolar localization in non-human primate (NHP) preimplantation embryos, but is cytoplasmic in NHP ESCs. Lin28 transcripts show a striking decline before mouse EGA, whereas LIN28 protein localizes to NPBs at the time of EGA. Following knockdown with a Lin28 morpholino, the majority of embryos arrest between the 2- and 4-cell stages and never develop to morula or blastocyst. Lin28 morpholino-injected embryos arrested at the 2-cell stage were not enriched with nucleophosmin at presumptive NPB sites, indicating that functional NPBs were not assembled. Based on these results, we propose that LIN28 is an essential factor of nucleologenesis during early embryonic development.

  3. sel-11 and cdc-42, two negative modulators of LIN-12/Notch activity in C. elegans.

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    Min Sung Choi

    Full Text Available BACKGROUND: LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer. METHODOLOGY/PRINCIPAL FINDINGS: We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification. CONCLUSIONS/SIGNIFICANCE: Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer.

  4. Lin28 and let-7 in the Metabolic Physiology of Aging.

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    Jun-Hao, Elwin Tan; Gupta, Renuka Ravi; Shyh-Chang, Ng

    2016-03-01

    The Lin28/let-7 molecular switch has emerged as a central regulator of growth signaling pathways and metabolic enzymes. Initially discovered to regulate developmental timing in the nematode, the Lin28/let-7 pathway of RNA regulation has gained prominence for its role in mammalian stem cells, cancer cells, tissue development, and aging. By regulating RNAs, the pathway coordinates cellular growth and cellular metabolism to influence metabolic physiology. Here, we review this regulatory mechanism and its impact on cancers, which reactivate Lin28, cardiovascular diseases, which implicate let-7, human genome-wide association studies (GWAS) of growth, and metabolic diseases, which implicate the Lin28/let-7 pathway. We also highlight questions relating to Barker's Hypothesis and the potential actions of the Lin28/let-7 pathway on programming long-lasting epigenetic effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Increased expression of Lin28B associates with poor prognosis in patients with oral squamous cell carcinoma.

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    Wu, Tianfu; Jia, Jun; Xiong, Xuepeng; He, Haijun; Bu, Linlin; Zhao, Zhili; Huang, Congfa; Zhang, Wenfeng

    2013-01-01

    Recent studies showed that incomplete cell reprogramming can transform cells into tumour-like cells. Lin28A is associated with fibroblast and sarcoma cell reprogramming, whereas its homologue Lin28B is associated with hematopoietic cell reprogramming. This study aimed to investigate the expression and prognostic difference between Lin28A and Lin28B in oral squamous cell carcinoma (OSCC). Expression level was assessed by immunohistochemistry and staining location was confirmed by immunofluorescence. Prognostic values were analysed and compared by the Kaplan-Meier analysis and uni and multivariate Cox regression models. Besides, in vitro cell assays and in vivo nude mice xenograft were used to demonstrate the influence of increased Lin28B expression in OSCC. Lin28A and Lin28B expression increased in OSCC, and co-expression of Lin28A and Lin28B showed no significant association with patient prognosis. Kaplan-Meier analysis showed that patients with high Lin28B but not Lin28A expression had lower overall survival (OS) rates than those with low Lin28B expression. Further Univariate analysis showed that patients with increased Lin28B expression had shorter disease-free survival (DFS) and shorter OS, while multivariate analysis showed Lin28B overexpression with TNM stage predicted poor prognosis in patients with OSCC. Besides, stable expressing Lin28B in oral cancer cells promoted cell migration, invasion, colony formation, in vivo proliferation and increased the expression of cancer suppressor miRNA let-7 targeted genes IL-6, HMGA2, the EMT markers Snail and Twist, the angiogenesis inducer VEGF, and the apoptosis inhibitor Survivin. These combined results indicate that Lin28B is a novel marker for predicting prognosis in patients with OSCC and may be a therapeutic target.

  6. Increased expression of Lin28B associates with poor prognosis in patients with oral squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Tianfu Wu

    Full Text Available Recent studies showed that incomplete cell reprogramming can transform cells into tumour-like cells. Lin28A is associated with fibroblast and sarcoma cell reprogramming, whereas its homologue Lin28B is associated with hematopoietic cell reprogramming. This study aimed to investigate the expression and prognostic difference between Lin28A and Lin28B in oral squamous cell carcinoma (OSCC. Expression level was assessed by immunohistochemistry and staining location was confirmed by immunofluorescence. Prognostic values were analysed and compared by the Kaplan-Meier analysis and uni and multivariate Cox regression models. Besides, in vitro cell assays and in vivo nude mice xenograft were used to demonstrate the influence of increased Lin28B expression in OSCC. Lin28A and Lin28B expression increased in OSCC, and co-expression of Lin28A and Lin28B showed no significant association with patient prognosis. Kaplan-Meier analysis showed that patients with high Lin28B but not Lin28A expression had lower overall survival (OS rates than those with low Lin28B expression. Further Univariate analysis showed that patients with increased Lin28B expression had shorter disease-free survival (DFS and shorter OS, while multivariate analysis showed Lin28B overexpression with TNM stage predicted poor prognosis in patients with OSCC. Besides, stable expressing Lin28B in oral cancer cells promoted cell migration, invasion, colony formation, in vivo proliferation and increased the expression of cancer suppressor miRNA let-7 targeted genes IL-6, HMGA2, the EMT markers Snail and Twist, the angiogenesis inducer VEGF, and the apoptosis inhibitor Survivin. These combined results indicate that Lin28B is a novel marker for predicting prognosis in patients with OSCC and may be a therapeutic target.

  7. Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine.

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    Chen, Ching-Huan; Luhur, Arthur; Sokol, Nicholas

    2015-10-15

    Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration. © 2015. Published by The Company of Biologists Ltd.

  8. The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in Caenorhabditis elegans.

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    Cristina Tocchini

    2014-08-01

    Full Text Available The mechanisms controlling cell fate determination and reprogramming are fundamental for development. A profound reprogramming, allowing the production of pluripotent cells in early embryos, takes place during the oocyte-to-embryo transition. To understand how the oocyte reprogramming potential is controlled, we sought Caenorhabditis elegans mutants in which embryonic transcription is initiated precociously in germ cells. This screen identified LIN-41, a TRIM-NHL protein and a component of the somatic heterochronic pathway, as a temporal regulator of pluripotency in the germline. We found that LIN-41 is expressed in the cytoplasm of developing oocytes, which, in lin-41 mutants, acquire pluripotent characteristics of embryonic cells and form teratomas. To understand LIN-41 function in the germline, we conducted structure-function studies. In contrast to other TRIM-NHL proteins, we found that LIN-41 is unlikely to function as an E3 ubiquitin ligase. Similar to other TRIM-NHL proteins, the somatic function of LIN-41 is thought to involve mRNA regulation. Surprisingly, we found that mutations predicted to disrupt the association of LIN-41 with mRNA, which otherwise compromise LIN-41 function in the heterochronic pathway in the soma, have only minor effects in the germline. Similarly, LIN-41-mediated repression of a key somatic mRNA target is dispensable for the germline function. Thus, LIN-41 appears to function in the germline and the soma via different molecular mechanisms. These studies provide the first insight into the mechanism inhibiting the onset of embryonic differentiation in developing oocytes, which is required to ensure a successful transition between generations.

  9. Distinct expression patterns predict differential roles of the miRNA-binding proteins, Lin28 and Lin28b, in the mouse testis: studies during postnatal development and in a model of hypogonadotropic hypogonadism.

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    Gaytan, Francisco; Sangiao-Alvarellos, Susana; Manfredi-Lozano, María; García-Galiano, David; Ruiz-Pino, Francisco; Romero-Ruiz, Antonio; León, Silvia; Morales, Concepción; Cordido, Fernando; Pinilla, Leonor; Tena-Sempere, Manuel

    2013-03-01

    Lin28 (also termed Lin28a) and Lin28b are related RNA-binding proteins, involved in the control of microRNA synthesis, especially of the let-7 family, with putative functions in early (embryo) development. However, their roles during postnatal maturation remain ill defined. Despite the general assumption that Lin28 and Lin28b share similar targets and functions, conclusive demonstration of such redundancy is still missing. In addition, recent observations suggest a role of Lin28 proteins in mammalian reproduction, which is yet to be defined. We document herein the patterns of RNA expression and protein distribution of Lin28 and Lin28b in mouse testis during postnatal development and in a model of hypogonadotropic hypogonadism as a result of inactivation of the kisspeptin receptor, Gpr54. Lin28 and Lin28b mRNAs were expressed in mouse testis across postnatal maturation, but their levels disparately varied between neonatal and pubertal periods, with peak Lin28 levels in infantile testes and sustained elevation of Lin28b mRNA in young adult male gonads, where relative levels of let-7a and let-7b miRNAs were significantly suppressed. In addition, Lin28 peptides displayed totally different patterns of cellular distribution in mouse testis: Lin28 was located in undifferentiated and type-A1 spermatogonia, whereas Lin28b was confined to spermatids and interstitial Leydig cells. These profiles were perturbed in Gpr54 null mouse testis, which showed preserved but irregular Lin28 signal and absence of Lin28b peptide, which was rescued by administration of gonadotropins, mainly hCG (as super-agonist of LH). In addition, increased relative levels of Lin28, but not Lin28b, mRNA and of let-7a/let-7b miRNAs were observed in Gpr54 KO mouse testes. Altogether, our data are the first to document the divergent patterns of cellular distribution and mRNA expression of Lin28 and Lin28b in the mouse testis along postnatal maturation and their alteration in a model of congenital

  10. Analysis of LIN28A in early human ovary development and as a candidate gene for primary ovarian insufficiency.

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    El-Khairi, Ranna; Parnaik, Rahul; Duncan, Andrew J; Lin, Lin; Gerrelli, Dianne; Dattani, Mehul T; Conway, Gerard S; Achermann, John C

    2012-04-04

    Lin28 proteins are emerging as important regulators of microRNAs in endocrine systems. Lin28a regulates primordial germ cell development and puberty timing in mice, whereas the related protein LIN28B is associated with age at menarche in genome-wide association studies in humans. Here, we studied expression of LIN28A and LIN28B in early human gonad development. LIN28A increased in the developing ovary between 6 and 9weeks post conception, but not in the developing testis. Immunohistochemistry demonstrated LIN28A in peripheral germ cells. LIN28B was expressed at lower levels in both tissues and did not increase with time. As disruption of Lin28a affects germ cell development in mice, LIN28A was considered a candidate gene for primary ovarian insufficiency (POI) in humans. However, no significant changes were found in 50 women studied. These findings show LIN28A is strongly expressed in germ cells during early human ovary development, but disruption of LIN28A is not a common cause of POI. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation.

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    Tummala, Ramakumar; Nadiminty, Nagalakshmi; Lou, Wei; Evans, Christopher P; Gao, Allen C

    2016-04-01

    Prostate cancer (PCa) is androgen-dependent initially and progresses to a castration-resistant state after androgen deprivation therapy. Treatment options for castration-resistant PCa include the potent second-generation anti-androgen enzalutamide or CYP17A1 inhibitor abiraterone. Recent clinical observations point to the development of resistance to these therapies which may be mediated by constitutively active alternative splice variants of the androgen receptor (AR). Sensitivity of LNCaP cells overexpressing Lin28 (LN-Lin28) to enzalutamide, abiraterone, or bicalutamide was compared to that of control LN-neo cells using cell growth assays, proliferation assays using MTT, anchorage-dependent clonogenic ability assays and soft agar assays. Ability of LN-Lin28 cells to maintain AR activation after treatment with enzalutamide, abiraterone, or bicalutamide was tested using immunofluorescence, Western blotting, ChIP assays, and qRT-PCR. Importance of Lin28 in enzalutamide resistance was assessed by the downregulation of Lin28 expression in C4-2B and 22Rv1 cells chronically treated with enzalutamide. Requirement for sustained AR signaling in LN-Lin28 cells was examined by the downregulation of either full length AR or AR-V7 using siRNA. We show that Lin28 promotes the development of resistance to currently used targeted therapeutics by enhancing the expression of AR splice variants such as AR-V7. PCa cells overexpressing Lin28 exhibit resistance to treatment with enzalutamide, abiraterone, or bicalutamide. Downregulation of Lin28 resensitizes enzalutamide-resistant PCa cells to enzalutamide treatment. We also show that the upregulation of splicing factors such as hnRNPA1 by Lin28 may mediate the enhanced generation of AR splice variants in Lin28-expressing cells. Our findings suggest that Lin28 plays a key role in the acquisition of resistance to AR-targeted therapies by PCa cells and establish the importance of Lin28 in PCa progression. © 2015 Wiley Periodicals, Inc.

  12. Bacterial diversity and real-time PCR based assessment of linA and linB gene distribution at hexachlorocyclohexane contaminated sites.

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    Lal, Devi; Jindal, Swati; Kumari, Hansi; Jit, Simran; Nigam, Aeshna; Sharma, Pooja; Kumari, Kirti; Lal, Rup

    2015-03-01

    The disposal of hexachlorocyclohexane (HCH) muck has created large number of HCH dumpsites all over the world from where the harmful HCH isomers are leaking into the environment. Bacteria have evolved at such contaminated sites that have the ability to degrade HCH. Degradation of various HCH isomers in bacterial strains is mediated primarily by two genes: linA and linB which encode dehydrochlorinase and haloalkane dehalogenase respectively. In this study we explored one such highly contaminated HCH dumpsite located in Lucknow, Uttar Pradesh, India. To assess the biostimulation potential of the contaminated site, microbial diversity study and real-time PCR based quantification of lin genes was carried out. The soil samples from dumpsite and surrounding areas were found to be highly contaminated with HCH residue levels as high as 1.8 × 10(5)  mg kg(-1). The residues were detected in areas upto 13 km from the dumpsite. Sphingomonads, Chromohalobacter, and Marinobacter were the dominant genera present at the dump-site. Role of Sphingomonads in HCH degradation has been well documented. The highest copy numbers of linA and linB genes as determined using real-time PCR were 6.2 × 10(4) and 5.3 × 10(5), respectively, were found in sample from the dump site. The presence of Sphingomonads, linA, and linB genes from HCH contaminated soil indicates the presence of indigenous bacterial communities capable of HCH degradation.

  13. Identification of MicroRNAs Regulating Reprogramming Factor LIN28 in Embryonic Stem Cells and Cancer Cells*

    Science.gov (United States)

    Zhong, Xiaomin; Li, Ning; Liang, Shun; Huang, Qihong; Coukos, George; Zhang, Lin

    2010-01-01

    LIN28 (a homologue of the Caenorhabditis elegans lin-28 gene) is an evolutionarily conserved RNA-binding protein and a master regulator controlling the pluripotency of embryonic stem cells. Together with OCT4, SOX2, and NANOG, LIN28 can reprogram somatic cells, producing induced pluripotent stem cells. Expression of LIN28 is highly restricted to embryonic stem cells and developing tissues. In human tumors, LIN28 is up-regulated and functions as an oncogene promoting malignant transformation and tumor progression. However, the mechanisms of transcriptional and post-transcriptional regulation of LIN28 are still largely unknown. To examine microRNAs (miRNAs) that repress LIN28 expression, a combined in silico prediction and miRNA library screening approach was used in the present study. Four miRNAs directly regulating LIN28 (let-7, mir-125, mir-9, and mir-30) were initially identified by this approach and further validated by quantitative RT-PCR, Western blot analysis, and a LIN28 3′-UTR reporter assay. We found that expression levels of these four miRNAs were clustered together and inversely correlated with LIN28 expression during embryonic stem cell differentiation. In addition, the expression of these miRNAs was remarkably lower in LIN28-positive tumor cells compared with LIN28-negative tumor cells. Importantly, we demonstrated that these miRNAs were able to regulate the expression and activity of let-7, mediated by LIN28. Taken together, our studies demonstrate that miRNAs let-7, mir-125, mir-9, and mir-30 directly repress LIN28 expression in embryonic stem and cancer cells. Global down-regulation of these miRNAs may be one of the mechanisms of LIN28 reactivation in human cancers. PMID:20947512

  14. Identification of microRNAs regulating reprogramming factor LIN28 in embryonic stem cells and cancer cells.

    Science.gov (United States)

    Zhong, Xiaomin; Li, Ning; Liang, Shun; Huang, Qihong; Coukos, George; Zhang, Lin

    2010-12-31

    LIN28 (a homologue of the Caenorhabditis elegans lin-28 gene) is an evolutionarily conserved RNA-binding protein and a master regulator controlling the pluripotency of embryonic stem cells. Together with OCT4, SOX2, and NANOG, LIN28 can reprogram somatic cells, producing induced pluripotent stem cells. Expression of LIN28 is highly restricted to embryonic stem cells and developing tissues. In human tumors, LIN28 is up-regulated and functions as an oncogene promoting malignant transformation and tumor progression. However, the mechanisms of transcriptional and post-transcriptional regulation of LIN28 are still largely unknown. To examine microRNAs (miRNAs) that repress LIN28 expression, a combined in silico prediction and miRNA library screening approach was used in the present study. Four miRNAs directly regulating LIN28 (let-7, mir-125, mir-9, and mir-30) were initially identified by this approach and further validated by quantitative RT-PCR, Western blot analysis, and a LIN28 3'-UTR reporter assay. We found that expression levels of these four miRNAs were clustered together and inversely correlated with LIN28 expression during embryonic stem cell differentiation. In addition, the expression of these miRNAs was remarkably lower in LIN28-positive tumor cells compared with LIN28-negative tumor cells. Importantly, we demonstrated that these miRNAs were able to regulate the expression and activity of let-7, mediated by LIN28. Taken together, our studies demonstrate that miRNAs let-7, mir-125, mir-9, and mir-30 directly repress LIN28 expression in embryonic stem and cancer cells. Global down-regulation of these miRNAs may be one of the mechanisms of LIN28 reactivation in human cancers.

  15. LIN28A is a suppressor of ER-associated translation in embryonic stem cells.

    Science.gov (United States)

    Cho, Jun; Chang, Hyeshik; Kwon, S Chul; Kim, Baekgyu; Kim, Yoosik; Choe, Junho; Ha, Minju; Kim, Yoon Ki; Kim, V Narry

    2012-11-09

    LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.

    Science.gov (United States)

    Zhu, Hao; Shah, Samar; Shyh-Chang, Ng; Shinoda, Gen; Einhorn, William S; Viswanathan, Srinivas R; Takeuchi, Ayumu; Grasemann, Corinna; Rinn, John L; Lopez, Mary F; Hirschhorn, Joel N; Palmert, Mark R; Daley, George Q

    2010-07-01

    Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway.

  17. Lin28: an emerging important oncogene connecting several aspects of cancer.

    Science.gov (United States)

    Wang, Hao; Zhao, Qin; Deng, Kaiyuan; Guo, Xiaoqiang; Xia, Jiazeng

    2016-03-01

    RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let-7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers.

  18. The relationship between Lin28 and the chemotherapy response of gastric cancer.

    Science.gov (United States)

    Teng, Rong Yue; Zhou, Ji Chun; Jiang, Zi Nong; Xu, Chao Yang; Li, Zi Duo; Wang, Qing Chuan; Xu, Chen Pu; Guo, Ju Feng; Shen, Jian Guo; Wang, Lin Bo

    2013-01-01

    The aim of the study reported here was to identify whether a stem cell biomarker, Lin28, may predict the pathologic tumor response to neoadjuvant chemotherapy for patients with locally advanced gastric cancer. The study enrolled 47 patients with gastric cancer who underwent neoadjuvant chemotherapy followed by surgery between July 2004 and March 2012. Cancer tissue was biopsied by gastroscopy and Lin28 expression in the tissue was measured by immunohistochemistry. Statistical analyses were performed to identify the relationship between Lin28 expression and tumor regression grade. Of the 47 cases, pathologic nonresponse was observed in 29 (61.7%) and pathologic response in 18 (38.3%). Receiver-operating characteristic curve analysis showed that the histoscore of Lin28 expression with 0.325 as a cutoff value could differentiate between pathologic response and nonresponse. Multivariable analysis showed that Lin28 expression was an independent predictive factor for pathologic response to neoadjuvant chemotherapy (P = 0.006). Lin28 expression was associated with pathologic tumor response in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. This may suggest that Lin28 can serve as a predictive biomarker for neoadjuvant chemotherapy in patients with gastric cancer.

  19. Determinants of mRNA recognition and translation regulation by Lin28.

    Science.gov (United States)

    Lei, Xin-Xiang; Xu, Jie; Ma, Wei; Qiao, Chong; Newman, Martin A; Hammond, Scott M; Huang, Yingqun

    2012-04-01

    Lin28 is critical for stem cell maintenance and is also associated with advanced human malignancies. Our recent genome-wide studies mark Lin28 as a master post-transcriptional regulator of a subset of messenger RNAs important for cell growth and metabolism. However, the molecular basis underpinning the selective mRNA target regulation is unclear. Here, we provide evidence that Lin28 recognizes a unique motif in multiple target mRNAs, characterized by a small but critical 'A' bulge flanked by two G:C base pairs embedded in a complex secondary structure. This motif mediates Lin28-dependent stimulation of translation. As Lin28 is also known to inhibit the biogenesis of a cohort of miRNAs including let-7, we propose that Lin28 binding to different RNA types (precursor miRNAs versus mRNAs) may facilitate recruitment of different co-factors, leading to distinct regulatory outcomes. Our findings uncover a putative yet unexpected motif that may constitute a mechanistic base for the multitude of functions regulated by Lin28 in both stem cells and cancer cells.

  20. Lin28 and let-7: roles and regulation in liver diseases.

    Science.gov (United States)

    McDaniel, Kelly; Hall, Chad; Sato, Keisaku; Lairmore, Terry; Marzioni, Marco; Glaser, Shannon; Meng, Fanyin; Alpini, Gianfranco

    2016-05-15

    The diagnosis and treatment of liver disease remain a major health concern worldwide because of the diverse etiologies of this disease. For this reason, new therapeutic targets are greatly needed to halt the progression of this damaging disease. Upon initiation of liver injury by viral infection, autoimmune disease or toxin, and/or hepatitis, chronic disease may develop, which can progress to cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma, liver failure, or death. The Lin28/lethal-7 (let-7) molecular switch has emerged as a central regulator of multiorgan injuries and cancer development. Lin28 is a stem cell marker vital to initiation or maintenance of a stem cell phenotype. Lin28 has not been extensively studied in the liver, despite its ability to induce tissue regeneration via reprogramming of oxidative enzymes in other tissues and its involvement with numerous upstream regulators and downstream targets in liver disease. Theoretically, overexpression of Lin28 in certain forms of liver disease could be a potential treatment that aids in liver regeneration. Alternatively, Lin28 has been implicated numerous times in the progression of diverse cancer types and is associated with increased severity of disease. In this case, Lin28 could be a potential inhibitory target to prevent malignant transformation in the liver. This review seeks to characterize the role of Lin28 in liver disease.

  1. The Lin28 cold-shock domain remodels pre-let-7 microRNA.

    Science.gov (United States)

    Mayr, Florian; Schütz, Anja; Döge, Nadine; Heinemann, Udo

    2012-08-01

    The RNA-binding protein Lin28 regulates the processing of a developmentally important group of microRNAs, the let-7 family. Lin28 blocks the biogenesis of let-7 in embryonic stem cells and thereby prevents differentiation. It was shown that both RNA-binding domains (RBDs) of this protein, the cold-shock domain (CSD) and the zinc-knuckle domain (ZKD) are indispensable for pri- or pre-let-7 binding and blocking its maturation. Here, we systematically examined the nucleic acid-binding preferences of the Lin28 RBDs and determined the crystal structure of the Lin28 CSD in the absence and presence of nucleic acids. Both RNA-binding domains bind to single-stranded nucleic acids with the ZKD mediating specific binding to a conserved GGAG motif and the CSD showing only limited sequence specificity. However, only the isolated Lin28 CSD, but not the ZKD, can bind with a reasonable affinity to pre-let-7 and thus is able to remodel the terminal loop of pre-let-7 including the Dicer cleavage site. Further mutagenesis studies reveal that the Lin28 CSD induces a conformational change in the terminal loop of pre-let-7 and thereby facilitates a subsequent specific binding of the Lin28 ZKD to the conserved GGAG motif.

  2. The heterochronic gene Lin28 regulates amphibian metamorphosis through disturbance of thyroid hormone function.

    Science.gov (United States)

    Faunes, Fernando; Gundermann, Daniel G; Muñoz, Rosana; Bruno, Renzo; Larraín, Juan

    2017-05-15

    Metamorphosis is a classic example of developmental transition, which involves important morphological and physiological changes that prepare the organism for the adult life. It has been very well established that amphibian metamorphosis is mainly controlled by Thyroid Hormone (TH). Here, we show that the heterochronic gene Lin28 is downregulated during Xenopus laevis metamorphosis. Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes. The delay in metamorphosis is rescued by incubation with exogenous TH, indicating that Lin28 works upstream or parallel to TH. High-throughput analyses performed before any delay on metamorphosis or change in TH signaling showed that overexpression of Lin28 reduces transcript levels of several hormones secreted by the pituitary, including the Thyroid-Stimulating Hormone (TSH), and regulates the expression of proteins involved in TH transport, metabolism and signaling, showing that Lin28 disrupts TH function at different levels. Our data demonstrates that the role of Lin28 in controlling developmental transitions is evolutionary conserved and establishes a functional interaction between Lin28 and thyroid hormone function introducing a new regulatory step in perinatal development with implications for our understanding of endocrine disorders. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. LIN28: A Stem Cell Factor with a Key Role in Pediatric Tumor Formation.

    Science.gov (United States)

    Carmel-Gross, Ilana; Bollag, Naomi; Armon, Leah; Urbach, Achia

    2016-03-01

    Differentiation and development are normally unidirectional processes in which progenitor/stem cells differentiate into more mature cells. Transformation of adult cells into cancer cells is accompanied in many cases by dedifferentiation of the adult cell, while differentiation failure of progenitor cells can result in the formation of unique type of cancers called pediatric cancer. LIN28A and its paralog LIN28B are pluripotent genes that are expressed mainly in stem/progenitor cells. Since the first identification of LIN28 in mammals, numerous studies demonstrated the general oncogenic features of these genes. In this review, we emphasize the unique role of LIN28 in pediatric tumor formation. We show, based on comprehensive literature screen and analysis of published microarray data, that LIN28 expression in pediatric tumors is even more common than in adult tumors, and discuss the possibility that in the case of pediatric cancers, LIN28 acts by preventing normal development/differentiation rather than by transformation of mature cells into cancer cells. Overall, this review highlights the role of LIN28 as a bridge point between embryonic development, stem cell biology, and cancer.

  4. The C. elegans hox gene lin-39 controls cell cycle progression during vulval development.

    Science.gov (United States)

    Roiz, Daniel; Escobar-Restrepo, Juan Miguel; Leu, Philipp; Hajnal, Alex

    2016-10-01

    Cell fate specification during organogenesis is usually followed by a phase of cell proliferation to produce the required number of differentiated cells. The Caenorhabditis elegans vulva is an excellent model to study how cell fate specification and cell proliferation are coordinated. The six vulval precursor cells (VPCs) are born at the first larval stage, but they arrest in the G1 phase of the cell cycle until the beginning of the third larval stage, when their fates are specified and the three proximal VPCs proliferate to generate 22 vulval cells. An epidermal growth factor (EGF) signal from the gonadal anchor cell combined with lateral DELTA/NOTCH signaling between the VPCs determine the primary (1°) and secondary (2°) fates, respectively. The hox gene lin-39 plays a key role in integrating these spatial patterning signals and in maintaining the VPCs as polarized epithelial cells. Using a fusion-defective eff-1(lf) mutation to keep the VPCs polarized, we find that VPCs lacking lin-39 can neither activate lateral NOTCH signaling nor proliferate. LIN-39 promotes cell cycle progression through two distinct mechanisms. First, LIN-39 maintains the VPCs competent to proliferate by inducing cdk-4 cdk and cye-1 cyclinE expression via a non-canonical HOX binding motif. Second, LIN-39 activates in the adjacent VPCs the NOTCH signaling pathway, which promotes VPC proliferation independently of LIN-39. The hox gene lin-39 is therefore a central node in a regulatory network coordinating VPC differentiation and proliferation.

  5. The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy.

    Science.gov (United States)

    Wang, L D; Rao, T N; Rowe, R G; Nguyen, P T; Sullivan, J L; Pearson, D S; Doulatov, S; Wu, L; Lindsley, R C; Zhu, H; DeAngelo, D J; Daley, G Q; Wagers, A J

    2015-06-01

    Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development leads to systemic mastocytosis (SM), a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused MC accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.

  6. LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells.

    Science.gov (United States)

    Yang, Jun; Bennett, Brian D; Luo, Shujun; Inoue, Kaoru; Grimm, Sara A; Schroth, Gary P; Bushel, Pierre R; Kinyamu, H Karimi; Archer, Trevor K

    2015-09-01

    LIN28 is an evolutionarily conserved RNA-binding protein with critical functions in developmental timing and cancer. However, the molecular mechanisms underlying LIN28's oncogenic properties are yet to be described. RNA-protein immunoprecipitation coupled with genome-wide sequencing (RIP-Seq) analysis revealed significant LIN28 binding within 843 mRNAs in breast cancer cells. Many of the LIN28-bound mRNAs are implicated in the regulation of RNA and cell metabolism. We identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28-interacting partner. Subsequently, we used a custom computational method to identify differentially spliced gene isoforms in LIN28 and hnRNP A1 small interfering RNA (siRNA)-treated cells. The results reveal that these proteins regulate alternative splicing and steady-state mRNA expression of genes implicated in aspects of breast cancer biology. Notably, cells lacking LIN28 undergo significant isoform switching of the ENAH gene, resulting in a decrease in the expression of the ENAH exon 11a isoform. The expression of ENAH isoform 11a has been shown to be elevated in breast cancers that express HER2. Intriguingly, analysis of publicly available array data from the Cancer Genome Atlas (TCGA) reveals that LIN28 expression in the HER2 subtype is significantly different from that in other breast cancer subtypes. Collectively, our data suggest that LIN28 may regulate splicing and gene expression programs that drive breast cancer subtype phenotypes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  7. LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

    Science.gov (United States)

    Yang, Jun; Bennett, Brian D.; Luo, Shujun; Inoue, Kaoru; Grimm, Sara A.; Schroth, Gary P.; Bushel, Pierre R.

    2015-01-01

    LIN28 is an evolutionarily conserved RNA-binding protein with critical functions in developmental timing and cancer. However, the molecular mechanisms underlying LIN28's oncogenic properties are yet to be described. RNA-protein immunoprecipitation coupled with genome-wide sequencing (RIP-Seq) analysis revealed significant LIN28 binding within 843 mRNAs in breast cancer cells. Many of the LIN28-bound mRNAs are implicated in the regulation of RNA and cell metabolism. We identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28-interacting partner. Subsequently, we used a custom computational method to identify differentially spliced gene isoforms in LIN28 and hnRNP A1 small interfering RNA (siRNA)-treated cells. The results reveal that these proteins regulate alternative splicing and steady-state mRNA expression of genes implicated in aspects of breast cancer biology. Notably, cells lacking LIN28 undergo significant isoform switching of the ENAH gene, resulting in a decrease in the expression of the ENAH exon 11a isoform. The expression of ENAH isoform 11a has been shown to be elevated in breast cancers that express HER2. Intriguingly, analysis of publicly available array data from the Cancer Genome Atlas (TCGA) reveals that LIN28 expression in the HER2 subtype is significantly different from that in other breast cancer subtypes. Collectively, our data suggest that LIN28 may regulate splicing and gene expression programs that drive breast cancer subtype phenotypes. PMID:26149387

  8. RNA-binding protein LIN28 is a sensitive marker of pediatric yolk sac tumors.

    Science.gov (United States)

    Feng, Shaoguang; Huang, Songsong; Tong, Yulong; Chen, Zhongliang; Shen, Delei; Wu, Dazhou; Lai, Xin-He; Chen, Xiaoming

    2016-08-01

    RNA-binding protein LIN28 is involved in maintaining the pluripotency of embryonic stem cells. It has been detected in different types of testicular and ovarian germ cell tumors (GCTs), but its status in pediatric YSTs (yolk sac tumors) is still unknown. The aim of this study was to determine the immunohistochemical profile of LIN28 in pediatric YSTs. Immunohistochemistry detection of LIN28 was performed in 22 cases of pediatric YSTs and 10 mature teratomas. The percentage of tumor cells stained was scored as 0, 1+ (1-30 % cells), 2+ (31-60 %), 3+ (61-90 %), and 4+ (>90 %). To compare its sensitive and specificity with alpha-fetoprotein (AFP), we also stained AFP in 22 cases of pediatric YSTs and 10 mature teratomas in children. LIN28 staining was high in all 22 pediatric yolk sac tumor (2+ in 1, 3+ in 1, and 4+ in 20), and weak staining of LIN28 was seen in 1 of 10 mature teratomas (1+), 9 of 10 mature teratomas were negative expression. However, the expression of AFP in pediatric YST was lower compared with Lin28 (- in 1, 1+ in 8, 2+ in 12, and 3+ in 1), and weak expression of AFP was seen in 2 of 10 mature teratomas (1+), 8 of 10 mature teratomas were negative. LIN28 had higher intensity expression than AFP in pediatric YSTs (P LIN28 is a sensitive marker for pediatric YSTs and it can be used to distinguish them from mature teratomas. LIN28 is likely to become a new and valuable biomarker for diagnosing of pediatric YST.

  9. Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events.

    Science.gov (United States)

    Parisi, Silvia; Passaro, Fabiana; Russo, Luigi; Musto, Anna; Navarra, Angelica; Romano, Simona; Petrosino, Giuseppe; Russo, Tommaso

    2017-03-01

    Lin28 RNA-binding proteins play important roles in pluripotent stem cells, but the regulation of their expression and the mechanisms underlying their functions are still not definitively understood. Here we address the above-mentioned issues in the first steps of mouse embryonic stem cell (ESC) differentiation. We observed that the expression of Lin28 genes is transiently induced soon after the exit of ESCs from the naive ground state and that this induction is due to the Hmga2-dependent engagement of Otx2 with enhancers present at both Lin28 gene loci. These mechanisms are crucial for Lin28 regulation, as demonstrated by the abolishment of the Lin28 accumulation in Otx2- or Hmga2-knockout cells compared to the control cells. We have also found that Lin28 controls Hmga2 expression levels during ESC differentiation through a let-7-independent mechanism. Indeed, we found that Lin28 proteins bind a highly conserved element in the 3' UTR of Hmga2 mRNA, and this provokes a down-regulation of its translation. This mechanism prevents the inappropriate accumulation of Hmga2 that would modify the proliferation and physiological apoptosis of differentiating ESCs. In summary, we demonstrated that during ESC differentiation, Lin28 transient induction is dependent on Otx2 and Hmga2 and prevents an inappropriate excessive rise of Hmga2 levels.-Parisi, S., Passaro, F., Russo, L., Musto, A., Navarra, A., Romano, S., Petrosino, G., Russo, T. Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events. © FASEB.

  10. The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells?

    Science.gov (United States)

    Aeckerle, N; Eildermann, K; Drummer, C; Ehmcke, J; Schweyer, S; Lerchl, A; Bergmann, M; Kliesch, S; Gromoll, J; Schlatt, S; Behr, R

    2012-10-01

    Mammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates (NHPs) and man, the identity of primate SSCs is unknown. In contrast, in mice, germ cell transplantation studies have functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analyzed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with that in mice. In the marmoset, LIN28 was strongly expressed in migratory primordial germ cells and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult NHP testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium consisting only of Sertoli cells and SSCs during their non-breeding season. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating an SSC identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and NHP spermatogonia and might be a marker for a rare SSC population in NHPs and man. Further characterization of the LIN28-positive population is required.

  11. RNA-binding protein LIN28 is a marker for testicular germ cell tumors.

    Science.gov (United States)

    Cao, Dengfeng; Allan, Robert W; Cheng, Liang; Peng, Yan; Guo, Charles C; Dahiya, Neha; Akhi, Shirin; Li, Jianping

    2011-05-01

    LIN28 is an RNA-binding protein involved in maintaining the pluripotency of embryonic stem cells. Using formalin-fixed, paraffin-embedded tissue blocks, we performed immunohistochemical staining of LIN28 in 103 primary and 81 metastatic testicular germ cell tumors (54 intratubular germ cell neoplasias, unclassified type; 49 primary and 20 metastatic classic seminomas; 35 primary and 24 metastatic embryonal carcinomas; 35 primary and 15 metastatic yolk sac tumors; 23 primary and 12 metastatic teratomas; 6 primary and 10 metastatic choriocarcinomas; and 5 spermatocytic seminomas). The percentage of tumor cell stained was scored as 0 (0%), 1+ (≤30%), 2+ (31%-60%), 3+ (61%-90%), and 4+ (>90%). We stained LIN28 in 327 non-germ cell tumors to determine its specificity. We also compared LIN28 with SALL4 (Sal-like 4) and OCT4 (octamer-binding transcription factor 4) in all germ cell tumors. The staining was cytoplasmic for LIN28 and nuclear for SALL4 and OCT4. Strong 4+ LIN28 staining was seen in all 54 intratubular germ cell neoplasias, 59 embryonal carcinomas, and 50 yolk sac tumors. Positive LIN28 staining was seen in all 69 classic seminomas (1+ in 3, 3+ in 3, and 4+ in 63) (63, strong). Variable staining of LIN28 was seen in 10 of 35 teratomas (1+ to 3+, weak to strong intensity), 12 of 16 choriocarcinomas (1+ to 4+, weak to strong intensity), and 1 of 5 spermatocytic seminomas (2+, weak). Only 10 of 327 non-germ cell tumors showed 1+ weak LIN28 staining. Therefore, LIN28 is a highly sensitive marker for testicular intratubular germ cell neoplasias, classic seminomas, embryonal carcinomas, and yolk sac tumors with relatively high specificity. LIN28 can be used as a diagnostic marker for these tumors and has demonstrated a similar level of diagnostic utility as SALL4 (except for a few classic seminomas), although it does not show an advantage over SALL4. The major advantage of LIN28 over OCT4 is in diagnosing yolk sac tumors (yolk sac tumors negative for OCT4

  12. LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro.

    Science.gov (United States)

    Balzer, Erica; Heine, Christian; Jiang, Qiang; Lee, Vivian M; Moss, Eric G

    2010-03-01

    LIN28 is an RNA-binding protein that is expressed in many developing tissues. It can block let-7 (Mirlet7) microRNA processing and help promote pluripotency. We have observed LIN28 expression in the developing mouse neural tube, colocalizing with SOX2, suggesting a role in neural development. To better understand its normal developmental function, we investigated LIN28 activity during neurogliogenesis in vitro, where the succession of neuronal to glial cell fates occurs as it does in vivo. LIN28 expression was high in undifferentiated cells, and was downregulated rapidly upon differentiation. Constitutive LIN28 expression caused a complete block of gliogenesis and an increase in neurogenesis. LIN28 expression was compatible with neuronal differentiation and did not increase proliferation. LIN28 caused significant changes in gene expression prior to any effect on let-7, notably on Igf2. Furthermore, a mutant LIN28 that permitted let-7 accumulation was still able to completely block gliogenesis. Thus, at least two biological activities of LIN28 are genetically separable and might involve distinct mechanisms. LIN28 can differentially promote and inhibit specific fates and does not function exclusively by blocking let-7 family microRNAs. Importantly, the role of LIN28 in cell fate succession in vertebrate cells is analogous to its activity as a developmental timing regulator in C. elegans.

  13. A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B.

    Science.gov (United States)

    Suzuki, Hiroshi I; Katsura, Akihiro; Miyazono, Kohei

    2015-09-01

    The precise control of microRNA (miRNA) biosynthesis is crucial for gene regulation. Lin28A and Lin28B are selective inhibitors of biogenesis of let-7 miRNAs involved in development and tumorigenesis. Lin28A selectively inhibits let-7 biogenesis through cytoplasmic uridylation of precursor let-7 by TUT4 terminal uridyl transferase and subsequent degradation by Dis3l2 exonuclease. However, a role of this uridylation pathway remains unclear in let-7 blockade by Lin28B, a paralog of Lin28A, while Lin28B is reported to engage a distinct mechanism in the nucleus to suppress let-7. Here we revisit a functional link between Lin28B and the uridylation pathway with a focus on let-7 metabolism in cancer cells. Both Lin28A and Lin28B interacted with Dis3l2 in the cytoplasm, and silencing of Dis3l2 upregulated uridylated pre-let-7 in both Lin28A- and Lin28B-expressing cancer cell lines. In addition, we found that amounts of let-7 precursors influenced intracellular localization of Lin28B. Furthermore, we found that MCPIP1 (Zc3h12a) ribonuclease was also involved in degradation of both non-uridylated and uridylated pre-let-7. Cancer transcriptome analysis showed association of expression levels of Lin28B and uridylation pathway components, TUT4 and Dis3l2, in various human cancer cells and hepatocellular carcinoma. Collectively, these results suggest that cytoplasmic uridylation pathway actively participates in blockade of let-7 biogenesis by Lin28B. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  14. Self-Similar Solutions to the Lin-Reissner-Tsien Equation%Lin- Reissner-Tsien方程的自相似解

    Institute of Scientific and Technical Information of China (English)

    J·郝泽曼; K·法拉菲路; R·A·冯歌德; 黄雅意

    2011-01-01

    The Lin-Reissner-Tsien equation describes unsteady transonic flows under the transonic approximation. The equation was reduced to an ordinary differential equation via a similarity transformation. The resulting equation was then solved analytically, and in some cases even exactly. Numerical simulations were provided for the cases in which there were no exact solutions. Traveling wave solutions were also obtained.%Lin-Reissner-Tsien方程描述了在跨音速近似下的不稳定跨音速流动.通过相似变换,将Lin-Reissner-Tsien方程简化为一个常微分方程.然后解析求解所得到的方程,并在某些情况下得到的正好是精确解.上述情况下无法得到精确解时,给出了数值模拟.还得到了行波解.

  15. Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity.

    Science.gov (United States)

    Ditadi, Andrea; de Coppi, Paolo; Picone, Olivier; Gautreau, Laetitia; Smati, Rim; Six, Emmanuelle; Bonhomme, Delphine; Ezine, Sophie; Frydman, René; Cavazzana-Calvo, Marina; André-Schmutz, Isabelle

    2009-04-23

    We have isolated c-Kit(+)Lin(-) cells from both human and murine amniotic fluid (AF) and investigated their hematopoietic potential. In vitro, the c-Kit(+)Lin(-) population in both species displayed a multilineage hematopoietic potential, as demonstrated by the generation of erythroid, myeloid, and lymphoid cells. In vivo, cells belonging to all 3 hematopoietic lineages were found after primary and secondary transplantation of murine c-Kit(+)Lin(-) cells into immunocompromised hosts, thus demonstrating the ability of these cells to self-renew. Gene expression analysis of c-Kit(+) cells isolated from murine AF confirmed these results. The presence of cells with similar characteristics in the surrounding amnion indicates the possible origin of AF c-Kit(+)Lin(-) cells. This is the first report showing that cells isolated from the AF do have hematopoietic potential; our results support the idea that AF may be a new source of stem cells for therapeutic applications.

  16. LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients.

    Science.gov (United States)

    Qin, Rong; Zhou, Jingxu; Chen, Chao; Xu, Tao; Yan, Yong; Ma, Yushui; Zheng, Zongli; Shen, Yiping; Lu, Yicheng; Fu, Da; Chen, Juxiang

    2014-01-01

    LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study aimed to examine the expression of LIN28 in glioma and correlate the results to patient outcome. We found that LIN28 expression was significantly higher in the group of patients with a poor prognosis compared to patients with a good prognosis by gene microarray. Log-rank analysis showed patients with higher LIN28 expression level in tumor had a shorter progression-free survival and overall survival times compared to those with lower LIN28 expression level. Similar results were also obtained from the tissue microarray analysis. Univariate and multivariate analyses showed high LIN28 expression was an independent prognostic factor for a shorter progression-free survival and overall survival in GBM patients. Furthermore in vitro experiments showed that down-regulation of LIN28 in U251 and U373 cells caused cell cycle arrest in the G1 phase, delayed cell proliferation, increased apoptosis, and resulted in fewer colonies compared to controls. Summarily, our data provides a potential target for cancer therapy as an approach to overcome the poor options currently available for GBM patients.

  17. The relationship between Lin28 and the chemotherapy response of gastric cancer

    Directory of Open Access Journals (Sweden)

    Teng RY

    2013-09-01

    Full Text Available Rong Yue Teng,1,* Ji Chun Zhou,1,* Zi Nong Jiang,2 Chao Yang Xu,3 Zi Duo Li,1 Qing Chuan Wang,1 Chen Pu Xu,1 Ju Feng Guo,1 Jian Guo Shen,1 Lin Bo Wang1,4 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 2Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 3Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing Liberal Art College, Shaoxing, 4Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, People's Republic of China *These authors contributed equally to this work Objective: The aim of the study reported here was to identify whether a stem cell biomarker, Lin28, may predict the pathologic tumor response to neoadjuvant chemotherapy for patients with locally advanced gastric cancer. Methods: The study enrolled 47 patients with gastric cancer who underwent neoadjuvant chemotherapy followed by surgery between July 2004 and March 2012. Cancer tissue was biopsied by gastroscopy and Lin28 expression in the tissue was measured by immunohistochemistry. Statistical analyses were performed to identify the relationship between Lin28 expression and tumor regression grade. Results: Of the 47 cases, pathologic nonresponse was observed in 29 (61.7% and pathologic response in 18 (38.3%. Receiver-operating characteristic curve analysis showed that the histoscore of Lin28 expression with 0.325 as a cutoff value could differentiate between pathologic response and nonresponse. Multivariable analysis showed that Lin28 expression was an independent predictive factor for pathologic response to neoadjuvant chemotherapy (P = 0.006. Conclusion: Lin28 expression was associated with pathologic tumor response in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. This may suggest that Lin28 can serve as a predictive biomarker for neoadjuvant

  18. LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients.

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    Rong Qin

    Full Text Available LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study aimed to examine the expression of LIN28 in glioma and correlate the results to patient outcome. We found that LIN28 expression was significantly higher in the group of patients with a poor prognosis compared to patients with a good prognosis by gene microarray. Log-rank analysis showed patients with higher LIN28 expression level in tumor had a shorter progression-free survival and overall survival times compared to those with lower LIN28 expression level. Similar results were also obtained from the tissue microarray analysis. Univariate and multivariate analyses showed high LIN28 expression was an independent prognostic factor for a shorter progression-free survival and overall survival in GBM patients. Furthermore in vitro experiments showed that down-regulation of LIN28 in U251 and U373 cells caused cell cycle arrest in the G1 phase, delayed cell proliferation, increased apoptosis, and resulted in fewer colonies compared to controls. Summarily, our data provides a potential target for cancer therapy as an approach to overcome the poor options currently available for GBM patients.

  19. Another Security Improvement over the Lin et al.'s E-voting Scheme

    Science.gov (United States)

    Asaar, Maryam Rajabzadeh; Mohajeri, Javad; Salmasizadeh, Mahmoud

    In 2003, Lin et al. have proposed an electronic voting scheme which can be utilized in large-scale elections, and claimed it detects double voting. But in this paper, by presenting an attack, we show that voters can successfully vote more than once without being detected. Hence, we propose a new modified scheme based on the Lin et al.'s scheme with the same efficiency to solve this weakness and analyze its security.

  20. Lin-Kernighan Heuristic Adaptation for the Generalized Traveling Salesman Problem

    CERN Document Server

    Karapetyan, Daniel

    2010-01-01

    Lin-Kernighan heuristic is known to be one of the most successful heuristics for the Traveling Salesman Problem (TSP). It has also proven its efficiency in application to some other problems. However, it was never applied to the the Generalized Traveling Salesman Problem (GTSP) though it has the same nature as TSP. In this paper we discuss possible adaptations of TSP heuristics for GTSP and focus on the case of Lin-Kernighan algorithm. At first, we provide an easy-to-understand description of the original Lin-Kernighan heuristic. Then we propose several adaptations, both trivial and complicated ones. Finally, we conduct a fair competition between all the variations of Lin-Kernighan adaptation and some other GTSP heuristics. It appears that our adaptation of Lin-Kernighan algorithm for GTSP reproduces the success of the original heuristic. Different variations of our adaptation outperform all other heuristics in a wide range of tradeoffs between solution quality and running time, making Lin-Kernighan the state...

  1. A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression

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    Robinson Triboulet

    2015-10-01

    Full Text Available Let-7 microRNAs (miRNAs are critical regulators of animal development, stem cell differentiation, glucose metabolism, and tumorigenesis. Mammalian genomes contain 12 let-7 isoforms that suppress expression of a common set of target mRNAs. LIN28 proteins selectively block let-7 biogenesis in undifferentiated cells and in cancer. The current model for coordinate let-7 repression involves the LIN28 cold-shock domain (CSD binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7 RNAs. Here, we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2, escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in development and disease.

  2. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR).

    Science.gov (United States)

    Korshunov, Andrey; Ryzhova, Marina; Jones, David T W; Northcott, Paul A; van Sluis, Peter; Volckmann, Richard; Koster, Jan; Versteeg, Rogier; Cowdrey, Cynthia; Perry, Arie; Picard, Daniel; Rosenblum, Marc; Giangaspero, Felice; Aronica, Eleonora; Schüller, Ulrich; Hasselblatt, Martin; Collins, V Peter; von Deimling, Andreas; Lichter, Peter; Huang, Annie; Pfister, Stefan M; Kool, Marcel

    2012-12-01

    Embryonal tumor with multilayered rosettes (ETMR, previously known as ETANTR) is a highly aggressive embryonal CNS tumor, which almost exclusively affects infants and is associated with a dismal prognosis. Accurate diagnosis is of critical clinical importance because of its poor response to current treatment protocols and its distinct biology. Amplification of the miRNA cluster at 19q13.42 has been identified previously as a genetic hallmark for ETMR, but an immunohistochemistry-based assay for clinical routine diagnostics [such as INI-1 for atypical teratoid rhabdoid tumor (AT/RT)] is still lacking. In this study, we screened for an ETMR-specific marker using a gene-expression profiling dataset of more than 1,400 brain tumors and identified LIN28A as a highly specific marker for ETMR. The encoded protein binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis. Using an LIN28A specific antibody, we carried out immunohistochemical analysis of LIN28A in more than 800 childhood brain-tumor samples and confirmed its high specificity for ETMR. Strong LIN28A immunoexpression was found in all 37 ETMR samples tested, whereas focal reactivity was only present in a small (6/50) proportion of AT/RT samples. All other pediatric brain tumors were completely LIN28A-negative. In summary, we established LIN28A immunohistochemistry as a highly sensitive and specific, rapid, inexpensive diagnostic tool for routine pathological verification of ETMR.

  3. Divergent LIN28-mRNA associations result in translational suppression upon the initiation of differentiation.

    Science.gov (United States)

    Tan, Shen Mynn; Altschuler, Gabriel; Zhao, Tian Yun; Ang, Haw Siang; Yang, Henry; Lim, Bing; Vardy, Leah; Hide, Winston; Thomson, Andrew M; Lareu, Ricky R

    2014-07-01

    LIN28 function is fundamental to the activity and behavior of human embryonic stem cells (hESCs) and induced pluripotent stem cells. Its main roles in these cell types are the regulation of translational efficiency and let-7 miRNA maturation. However, LIN28-associated mRNA cargo shifting and resultant regulation of translational efficiency upon the initiation of differentiation remain unknown. An RNA-immunoprecipitation and microarray analysis protocol, eRIP, that has high specificity and sensitivity was developed to test endogenous LIN28-associated mRNA cargo shifting. A combined eRIP and polysome analysis of early stage differentiation of hESCs with two distinct differentiation cues revealed close similarities between the dynamics of LIN28 association and translational modulation of genes involved in the Wnt signaling, cell cycle, RNA metabolism and proteasomal pathways. Our data demonstrate that change in translational efficiency is a major contributor to early stages of differentiation of hESCs, in which LIN28 plays a central role. This implies that eRIP analysis of LIN28-associated RNA cargoes may be used for rapid functional quality control of pluripotent stem cells under manufacture for therapeutic applications. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression.

    Science.gov (United States)

    Triboulet, Robinson; Pirouz, Mehdi; Gregory, Richard I

    2015-10-13

    Let-7 microRNAs (miRNAs) are critical regulators of animal development, stem cell differentiation, glucose metabolism, and tumorigenesis. Mammalian genomes contain 12 let-7 isoforms that suppress expression of a common set of target mRNAs. LIN28 proteins selectively block let-7 biogenesis in undifferentiated cells and in cancer. The current model for coordinate let-7 repression involves the LIN28 cold-shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here, we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in development and disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Novel LINS1 missense mutation in a family with non-syndromic intellectual disability.

    Science.gov (United States)

    Sheth, Jayesh; Ranjan, Gyan; Shah, Krati; Bhavsar, Riddhi; Sheth, Frenny

    2017-04-01

    Newer sequencing technologies decipher molecular variations and increase the knowledge of pathogenesis of complex diseases like intellectual disability (ID), affecting 2-3% of the population. We report a novel family with a missense mutation in LINS1 as a cause for non-syndromic ID. Clinical exome sequencing for ID related genes carried out for a male with dysmorphism, mutism, and cognitive delay was uninformative. Subsequently, "pathogenic" and "likely pathogenic" variants associated with other inherited disorders were searched for as secondary findings. Further, PCR-RFLP carried out in other family members confirmed the result. A novel missense variant (c.937G>A) in exon 5 of LINS1 was detected in the proband. His affected elder brother was homozygous and the parents were heterozygous respectively, for the mutation. No mutation was observed in his unaffected sister. Mutations in LINS1 were suspected in this non-syndromic ID case with mutism. LINS1 alterations affect ELAV1 expression and result in reduction in the commissural axonal growth, thus affecting peripheral and central neuronal function. LINS1 acts in association with β-catenin to influence WNT1 signaling. It is hypothesized that mutations in LINS1 may alter HuR expression during neural differentiation, leading to ID in humans. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. A potential regulatory loop between Lin28B:miR‑212 in androgen-independent prostate cancer.

    Science.gov (United States)

    Borrego-Diaz, Emma; Powers, Benjamin C; Azizov, Vugar; Lovell, Scott; Reyes, Ruben; Chapman, Bradley; Tawfik, Ossama; McGregor, Douglas; Diaz, Francisco J; Wang, Xinkun; Veldhuizen, Peter Van

    2014-12-01

    Lin28 is a family of RNA binding proteins and microRNA regulators. Two members of this family have been identified: Lin28A and Lin28B, which are encoded by genes localized in different chromosomes but share a high degree of sequence identity. The role of Lin28B in androgen-independent prostate cancer (AIPC) is not well understood. Lin28B is expressed in all grades of prostatic carcinomas and prostate cancer cell lines, but not in normal prostate tissue. In this study we found that Lin28B co-localized in the nucleus and cytoplasm of the DU145 AIPC. The expression of Lin28B protein positively correlated with the expression of the c-Myc protein in the prostate cancer cell lines and silencing of Lin28B also correlated with a lower expression of the c-Myc protein, but not with the downregulation of c-Myc messenger RNA (mRNA) in the DU145 AIPC cells. We hypothesized that Lin28B regul-ates the expression of c-Myc protein by altering intermediate c-Myc suppressors. Therefore, a microRNA profile of DU145 cells was performed after Lin28B siRNA silencing. Nineteen microRNAs were upregulated and eleven microRNAs were downregulated. The most upregulated microRNAs were miR-212 and miR-2278. Prior reports have found that miR-212 is suppressed in prostate cancer. We then ran TargetScan software to find potential target mRNAs of miR-212 and miR-2278, and it predicted Lin28B mRNA as a potential target of miR-212, but not miR-2278. TargetScan also predicted that c-Myc mRNA is not a potential target of miR-212 or miR-2278. These observations suggest that Lin28B:miR-212 may work as a regulatory loop in androgen-independent prostate cancer. Furthermore, we report a predictive 2-fold symmetric model generated by the superposition of the Lin28A structure onto the I-TASSER model of Lin28B. This structural model of Lin28B suggests that it shows unique microRNA binding characteristics. Thus, if Lin28B were to bind miRNAs in a manner similar to Lin28A, conformational changes would be

  7. A potential regulatory loop between Lin28B:miR-212 in androgen-independent prostate cancer

    Science.gov (United States)

    BORREGO-DIAZ, EMMA; POWERS, BENJAMIN C.; AZIZOV, VUGAR; LOVELL, SCOTT; REYES, RUBEN; CHAPMAN, BRADLEY; TAWFIK, OSSAMA; McGREGOR, DOUGLAS; DIAZ, FRANCISCO J.; WANG, XINKUN; VAN VELDHUIZEN, PETER

    2014-01-01

    Lin28 is a family of RNA binding proteins and microRNA regulators. Two members of this family have been identified: Lin28A and Lin28B, which are encoded by genes localized in different chromosomes but share a high degree of sequence identity. The role of Lin28B in androgen-independent prostate cancer (AIPC) is not well understood. Lin28B is expressed in all grades of prostatic carcinomas and prostate cancer cell lines, but not in normal prostate tissue. In this study we found that Lin28B co-localized in the nucleus and cytoplasm of the DU145 AIPC. The expression of Lin28B protein positively correlated with the expression of the c-Myc protein in the prostate cancer cell lines and silencing of Lin28B also correlated with a lower expression of the c-Myc protein, but not with the downregulation of c-Myc messenger RNA (mRNA) in the DU145 AIPC cells. We hypothesized that Lin28B regulates the expression of c-Myc protein by altering intermediate c-Myc suppressors. Therefore, a microRNA profile of DU145 cells was performed after Lin28B siRNA silencing. Nineteen microRNAs were upregulated and eleven microRNAs were downregulated. The most upregulated microRNAs were miR-212 and miR-2278. Prior reports have found that miR-212 is suppressed in prostate cancer. We then ran TargetScan software to find potential target mRNAs of miR-212 and miR-2278, and it predicted Lin28B mRNA as a potential target of miR-212, but not miR-2278. TargetScan also predicted that c-Myc mRNA is not a potential target of miR-212 or miR-2278. These observations suggest that Lin28B:miR-212 may work as a regulatory loop in androgen-independent prostate cancer. Furthermore, we report a predictive 2-fold symmetric model generated by the superposition of the Lin28A structure onto the I-TASSER model of Lin28B. This structural model of Lin28B suggests that it shows unique microRNA binding characteristics. Thus, if Lin28B were to bind miRNAs in a manner similar to Lin28A, conformational changes would be necessary

  8. LIN28 expression and prognostic value in hepatocellular carcinoma patients who meet the Milan criteria and undergo hepatectomy.

    Science.gov (United States)

    Qiu, Ji-Liang; Huang, Pin-Zhu; You, Jing-Hong; Zou, Ru-Hai; Wang, Li; Hong, Jian; Li, Bin-Kui; Zhou, Kai; Yuan, Yun-Fei

    2012-05-01

    Stem cell marker LIN28, related closely with SOX2 and OCT4, has been studied as a biomarker for the maintainance of pluripotent cells in several malignancies. Our previous study showed that SOX2 and OCT4 were negative predictors for hepatocellular carcinoma (HCC). However, the predictive value of LIN28 in HCC outcome is still undetermined. We hypothesized that LIN28 may also play a role as a biomarker for HCC. To test this hypothesis, we examined the expression of LIN28 in 129 radically resected HCC tissues using reverse transcription-polymerase chain reaction and analyzed the association of LIN28 expression with clinicopathologic features and prognosis. Our study showed that LIN28 was expressed at a higher frequency in tumor tissues than in non-HCC tissues (45.0% vs. 21.7%, P = 0.020). Moreover, LIN28 expression was significantly increased in cases with large tumor size (P = 0.010). Univariate analysis did not reveal a significant correlation between LIN28 expression and overall survival or recurrence-free survival. For HCC patients who met the Milan criteria, stratified analysis revealed shorter overall survival (P = 0.007) and recurrence-free survival (P LIN28 expression compared to those with no detectable LIN28 expression. Furthermore, multivariate analysis revealed that LIN28 was a negative independent predictor for both overall survival (hazard ratio= 7.093, P = 0.017) and recurrence-free survival (hazard ratio=5.518, P = 0.004) in patients who met the Milan criteria. Taken together, our results suggest that LIN28 identifies low-risk and high-risk subsets of HCC patients meeting the Milan criteria who undergo hepatectomy.

  9. A cell-specific enhancer that specifies lin-3 expression in the C. elegans anchor cell for vulval development.

    Science.gov (United States)

    Hwang, Byung Joon; Sternberg, Paul W

    2004-01-01

    During C. elegans vulval development, the anchor cell (AC) in the somatic gonad expresses lin-3, activating the EGF receptor signaling pathway in vulval precursor cells (VPCs) and thereby inducing and patterning VPCs. Previous studies with lin-3 mutants and transgene expression have revealed that the level of LIN-3 in the AC must be precisely regulated for proper vulval development. To understand how lin-3 expression is achieved in the AC, we identified a 59 bp lin-3 enhancer sufficient to activate lin-3 transcription solely in the AC. The enhancer contains two E-box elements, and one FTZ-F1 nuclear hormone receptor (NHR) binding site that is mutated in a vulvaless mutant, lin-3(e1417). Mutagenesis studies show that both E-boxes and the NHR binding site are necessary to express lin-3 in the AC. In vitro DNA-binding studies and in vivo functional assays indicate that distinct trans-acting factors, including the E-protein/Daughterless homolog HLH-2 and unidentified nuclear hormone receptor(s), are necessary for lin-3 transcription in the AC and thus are involved in vulval development.

  10. SDF1-a facilitates Lin-/Sca1+ cell homing following murine experimental cerebral ischemia.

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    J Mocco

    Full Text Available BACKGROUND: Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized. METHODS: Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin-/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade. RESULTS: Bone marrow demonstrated a significant increase in Lin-/Sca1+ cell counts at 24 hrs (272 ± 60%; P<0.05 vs sham. Mobilization of Lin-/Sca1+ cells to blood was significantly elevated at 24 hrs (607 ± 159%; P<0.05. Serum SDF1-A levels were significant at 24 hrs (Sham (103 ± 14, 4 hrs (94 ± 20%, p = NS and 24 hrs (130 ± 17; p<0.05. Brain SDF1-A levels were significantly elevated at both 4 hrs and 24 hrs (113 ± 7 pg/ml and 112 ± 10 pg/ml, respectively; p<0.05 versus sham 76 ± 11 pg/ml. Following administration of an SDF1-A antibody, Lin-/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536 ± 65, blood cell count: 127 ± 24; p<0.05 versus placebo. Exogenously administered Lin-/Sca1+ cells resulted in a significant reduction in infarct volume: 42 ± 5% (stroke alone, versus 21 ± 15% (Stroke+Lin-/Sca1+ cells, and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin-/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin-/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10 ± 4 vs 0.7 ± 1, p<0.05. CONCLUSIONS: SDF1-A appears to play a critical role in modulating Lin-/Sca1+ cell migration to ischemic brain.

  11. SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

    Science.gov (United States)

    Cimadamore, Flavio; Amador-Arjona, Alejandro; Chen, Connie; Huang, Chun-Teng; Terskikh, Alexey V.

    2013-01-01

    The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cell-derived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2–LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential. PMID:23884650

  12. SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors.

    Science.gov (United States)

    Cimadamore, Flavio; Amador-Arjona, Alejandro; Chen, Connie; Huang, Chun-Teng; Terskikh, Alexey V

    2013-08-06

    The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cell-derived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.

  13. Bistable Switch in let-7 miRNA Biogenesis Pathway Involving Lin28

    Directory of Open Access Journals (Sweden)

    Fei Shi

    2014-10-01

    Full Text Available miRNAs are small noncoding RNAs capable of regulating gene expression at the post-transcriptional level. A growing body of evidence demonstrated that let-7 family of miRNAs, as one of the highly conserved miRNAs, plays an important role in cell differentiation and development, as well as tumor suppressor function depending on their levels of expression. To explore the physiological significance of let-7 in regulating cell fate decisions, we present a coarse grained model of let-7 biogenesis network, in which let-7 and its regulator Lin28 inhibit mutually. The dynamics of this minimal network architecture indicates that, as the concentration of Lin28 increases, the system undergoes a transition from monostability to a bistability and then to a one-way switch with increasing strength of positive feedback of let-7, while in the absence of Lin28 inhibition, the system loses bistability. Moreover, the ratio of degradation rates of let-7 and Lin28 is critical for the switching sensitivity and resistance to stimulus fluctuations. These findings may highlight why let-7 is required for normal gene expression in the context of embryonic development and oncogenesis, which will facilitate the development of approaches to exploit this regulatory pathway by manipulating Lin28/let-7 axis for novel treatments of human diseases.

  14. H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance.

    Science.gov (United States)

    Peng, Fei; Li, Ting-Ting; Wang, Kai-Li; Xiao, Guo-Qing; Wang, Ju-Hong; Zhao, Hai-Dong; Kang, Zhi-Jie; Fan, Wen-Jun; Zhu, Li-Li; Li, Mei; Cui, Bai; Zheng, Fei-Meng; Wang, Hong-Jiang; Lam, Eric W-F; Wang, Bo; Xu, Jie; Liu, Quentin

    2017-01-19

    Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.

  15. Molecular basis for interaction of let-7 microRNAs with Lin28

    Science.gov (United States)

    Nam, Yunsun; Chen, Casandra; Gregory, Richard I; Chou, James J; Sliz, Piotr

    2011-01-01

    SUMMARY MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression. Among these, members of the let-7 miRNA family control many cell fate determination genes to influence pluripotency, differentiation, and transformation. Lin28 is a specific, post-transcriptional inhibitor of let-7 biogenesis. We report crystal structures of mouse Lin28 in complex with sequences from let-7d, let-7-f1, and let-7g precursors. The two folded domains of Lin28 recognize two distinct regions of the RNA and are sufficient for inhibition of let-7 in vivo. We also show by NMR spectroscopy that the linker connecting the two folded domains is flexible, accommodating Lin28 binding to diverse let-7 family members. Protein-RNA complex formation imposes specific conformations on both components that could affect downstream recognition by other processing factors. Our data provide a molecular explanation for Lin28 specificity and a model for how it regulates let-7. PMID:22078496

  16. Bistable switch in let-7 miRNA biogenesis pathway involving Lin28.

    Science.gov (United States)

    Shi, Fei; Yu, Wenbao; Wang, Xia

    2014-10-21

    miRNAs are small noncoding RNAs capable of regulating gene expression at the post-transcriptional level. A growing body of evidence demonstrated that let-7 family of miRNAs, as one of the highly conserved miRNAs, plays an important role in cell differentiation and development, as well as tumor suppressor function depending on their levels of expression. To explore the physiological significance of let-7 in regulating cell fate decisions, we present a coarse grained model of let-7 biogenesis network, in which let-7 and its regulator Lin28 inhibit mutually. The dynamics of this minimal network architecture indicates that, as the concentration of Lin28 increases, the system undergoes a transition from monostability to a bistability and then to a one-way switch with increasing strength of positive feedback of let-7, while in the absence of Lin28 inhibition, the system loses bistability. Moreover, the ratio of degradation rates of let-7 and Lin28 is critical for the switching sensitivity and resistance to stimulus fluctuations. These findings may highlight why let-7 is required for normal gene expression in the context of embryonic development and oncogenesis, which will facilitate the development of approaches to exploit this regulatory pathway by manipulating Lin28/let-7 axis for novel treatments of human diseases.

  17. Molecular Basis for Interaction of let-7 MicroRNAs with Lin28

    Energy Technology Data Exchange (ETDEWEB)

    Nam, Yunsun; Chen, Casandra; Gregory, Richard I.; Chou, James J.; Sliz, Piotr (Harvard-Med)

    2012-02-06

    MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression. Among these, members of the let-7 miRNA family control many cell-fate determination genes to influence pluripotency, differentiation, and transformation. Lin28 is a specific, posttranscriptional inhibitor of let-7 biogenesis. We report crystal structures of mouse Lin28 in complex with sequences from let-7d, let-7-f1, and let-7g precursors. The two folded domains of Lin28 recognize two distinct regions of the RNA and are sufficient for inhibition of let-7 in vivo. We also show by NMR spectroscopy that the linker connecting the two folded domains is flexible, accommodating Lin28 binding to diverse let-7 family members. Protein-RNA complex formation imposes specific conformations on both components that could affect downstream recognition by other processing factors. Our data provide a molecular explanation for Lin28 specificity and a model for how it regulates let-7.

  18. νLIN6: An Integrated Mobility Protocol in IPv6

    Science.gov (United States)

    Banno, Ayumi; Teraoka, Fumio

    This paper proposes a protocol called νLIN6 which supports both network mobility and host mobility in IPv6. There are several proposals to support network mobility and host mobility. Network Mobility (NEMO) Basic Support Protocol has several problems such as pinball routing, large header overhead due to multiple levels of tunneling, and a single point of failure. Optimized NEMO (ONEMO) and Mobile IP with Address Translation (MAT) are solutions to provide route optimization, but they generate a lot of signaling messages at a handover. In νLIN6, packet relay is required only once regardless of the nested level in network mobility while optimal routing is always provided in host mobility. A fixedsized extension header is used in network mobility while there is no header overhead in host mobility. νLIN6 is more tolerant of network failure and mobility agent failure than NEMO Basic Support Protocol. It also allows ordinary IPv6 nodes to communicate with mobile nodes and nodes in the mobile network. We implemented νLIN6 on NetBSD 2.0 Release. Our measurement results showed νLIN6 can provide host mobility and network mobility with low overhead.

  19. Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Shu-Wen Cheng

    Full Text Available By using an expressed sequence tag bioinformatic algorithm, we identified that Lin28 homolog B (Lin28B may have an oncofetal expression pattern which may facilitate detecting cancer cells in adults. It is also reported to be a potential marker for cancer stem cells. Therefore, we sought to verify oncofetal-stemness characters of Lin28B and test its potential as a circulating cancer stem cell-like marker in adult HCC patients. Lin28B mRNA was examined in a panel of fetal tissue, adult tissue and tumors. Lin28B was over-expressed or knocked down in HepG2 cells to evaluate its potential as a stem cell-like marker. RT-qPCR for Lin28B was performed in the peripheral blood mononuclear cells from patients with HCC receiving surgery (n=96 and non-HCC controls (n=60 and analyzed its clinical significance. Lin28B showed an oncofetal expression pattern. Its overexpression could upregulate stemness markers (OCT4, Nanog and SOX2 and enhance tumorsphere formation in vitro. Lin28B knockdown had opposite effects. Circulating Lin28B was detected in peripheral blood mononuclear cells in 3 cases (5% of non-HCC controls and 32 cases (33.3% of HCC patients. In HCC patients, circulating Lin28B was associated with high tumor grade (P=0.046, large size (P=0.005, high AJCC stage (P=0.044 and BCLC stage (P=0.017. Circulating Lin28B was significantly associated with decreased recurrence-free survival (P<0.001. Circulating Lin28B separated early stage HCC into 2 recurrence-free survival curves (P=0.003. In multivariate analysis, circulating Lin28B was an independent variable associated with early recurrence (P=0.045 and recurrence in early stage HCC (P=0.006. In conclusion, the oncofetal gene Lin28B is a potential oncofetal cancer-stem-cell-like circulating tumor cell marker that correlates with HCC recurrence after hepatectomy. Circulating Lin28B could refine early AJCC stages. Our finding supports the possible use of a TNMC (C for circulating tumor cells staging system

  20. Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement.

    Science.gov (United States)

    Hao, Yuanyuan; Lu, Qun; Yang, Guodong; Ma, Aiqun

    2016-10-28

    Myocardial remodeling and cardiac dysfunction prevention may represent a therapeutic approach to reduce mortality in patients with myocardial infarction (MI). We investigated the effects of Lin28a in experimental MI models, as well as the mechanisms underlying these effects. Left anterior descending (LAD) coronary artery ligation was used to construct an MI-induced injury model. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of Lin28a against MI-induced injury. Lin28a significantly inhibited left ventricular remodeling and cardiac dysfunction after MI, as demonstrated via echocardiography and hemodynamic measurements. Lin28a reduced cardiac enzyme and inflammatory marker release in mice subjected to MI-induced injury. The mechanisms underlying the protective effects of Lin28a against MI-induced injury were associated with autophagy enhancements and apoptosis inhibition. Consistent with these findings, Lin28a knockdown aggravated cardiac remodeling and dysfunction after MI-induced injury. Lin28a knockdown also inhibited cardiomyocyte autophagy and increased cardiomyocyte apoptosis in mice subjected to MI-induced injury. Interestingly, Sirt1 knockdown abolished the protective effects of Lin28a against cardiac remodeling and dysfunction after MI, and Lin28a failed to increase the numbers of GFP-LC3-positive punctae and decrease aggresome and p62 accumulation in Sirt1-knockdown neonatal cardiomyocytes subjected to hypoxia-induced injury. Lin28a inhibits cardiac remodeling, improves cardiac function, and reduces cardiac enzyme and inflammatory marker release after MI. Lin28a also up-regulates cardiomyocyte autophagy and inhibits cardiomyocyte apoptosis through Sirt1 activation. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Stepwise assembly of multiple Lin28 proteins on the terminal loop of let-7 miRNA precursors.

    Science.gov (United States)

    Desjardins, Alexandre; Bouvette, Jonathan; Legault, Pascale

    2014-04-01

    Lin28 inhibits the biogenesis of let-7 miRNAs through direct interactions with let-7 precursors. Previous studies have described seemingly inconsistent Lin28 binding sites on pre-let-7 RNAs. Here, we reconcile these data by examining the binding mechanism of Lin28 to the terminal loop of pre-let-7g (TL-let-7g) using biochemical and biophysical methods. First, we investigate Lin28 binding to TL-let-7g variants and short RNA fragments and identify three independent binding sites for Lin28 on TL-let-7g. We then determine that Lin28 assembles in a stepwise manner on TL-let-7g to form a stable 1:3 complex. We show that the cold-shock domain (CSD) of Lin28 is responsible for remodelling the terminal loop of TL-let-7g, whereas the NCp7-like domain facilitates the initial binding of Lin28 to TL-let-7g. This stable binding of multiple Lin28 molecules to the terminal loop of pre-let-7g extends to other precursors of the let-7 family, but not to other pre-miRNAs tested. We propose a model for stepwise assembly of the 1:1, 1:2 and 1:3 pre-let-7g/Lin28 complexes. Stepwise multimerization of Lin28 on pre-let-7 is required for maximum inhibition of Dicer cleavage for a least one member of the let-7 family and may be important for orchestrating the activity of the several factors that regulate let-7 biogenesis.

  2. LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary.

    Science.gov (United States)

    Childs, Andrew J; Kinnell, Hazel L; He, Jing; Anderson, Richard A

    2012-09-01

    Germ cell development requires timely transition from primordial germ cell (PGC) self-renewal to meiotic differentiation. This is associated with widespread changes in gene expression, including downregulation of stem cell-associated genes, such as OCT4 and KIT, and upregulation of markers of germ cell differentiation and meiosis, such as VASA, STRA8, and SYCP3. The stem cell-expressed RNA-binding protein Lin28 has recently been demonstrated to be essential for PGC specification in mice, and LIN28 is expressed in human germ cell tumors with phenotypic similarities to human fetal germ cells. We have therefore examined the expression of LIN28 during normal germ cell development in the human fetal ovary, from the PGC stage, through meiosis to the initiation of follicle formation. LIN28 transcript levels were highest when the gonad contained only PGCs, and decreased significantly with increasing gestation, coincident with the onset of germ cell differentiation. Immunohistochemistry revealed LIN28 protein expression to be germ cell-specific at all stages examined. All PGCs expressed LIN28, but at later gestations expression was restricted to a subpopulation of germ cells, which we demonstrate to be primordial and premeiotic germ cells based on immunofluorescent colocalization of LIN28 and OCT4, and absence of overlap with the meiosis marker SYCP3. We also demonstrate the expression of the LIN28 target precursor pri-microRNA transcripts pri-LET7a/f/d and pri-LET-7g in the human fetal ovary, and that expression of these is highest at the PGC stage, mirroring that of LIN28. The spatial and temporal restriction of LIN28 expression and coincident peaks of expression of LIN28 and target pri-microRNAs suggest important roles for this protein in the maintenance of the germline stem cell state and the regulation of microRNA activity in the developing human ovary.

  3. Run-time system based on LinSERCANS and Soft-PLC

    Institute of Scientific and Technical Information of China (English)

    Cunfeng KANG; Chong WANG; Chunmin MA; Xudong HUANG; Renyuan FEI

    2009-01-01

    Soft-PLC with open architecture is the direction of development in industrial automation. This paper discusses the method of communication between the interface functions of LinSERCANS under RTLinux and the external library of Soft-PLC under Windows. Based on the API HOOK theory, the communication between the interface functions of LinSERCANS and the external libraries of Soft-PLC is set up and it solves the calling functions of dynamic link libraries in different operation systems. It is able to combine LinSERCANS with the Soft-PLC, and a run-time system is developed based on the interface technology of the serial real-time communication system (SERCOS) and technology of soft-PLC. This run-time system has been used in all electronic injection molding machines and works very well.

  4. Lin Zhichun's Contributions to the Study of Ancient World History in China

    Institute of Scientific and Technical Information of China (English)

    Yan; Shaoxiang

    2015-01-01

    Lin Zhichun (林志纯, 1910-2007, henceforthreferred to as Lin, but popularly known by hispen name of Ri Zhi), was a famous historian ofancient world history in China. Born in Fujian,he was enrolled in The Great China Universityin 1939 as a junior college student, and becamean undergraduate in 1941. Lin probably knewwhat he would do after graduation and learntEnglish, Russian and Latin in the university.1But the turmoil in China in the next 10 years(Japanese invasion of China since 1937 and thenthe Liberation War) made his life rather hard andhe had to move between Shanghai, Beijing and Shenyang successively in order tosupport himself. However, he tried to carry out his researches on Chinese history andpublished some articles since 1934.

  5. Mortier de fibres de lin : applications possibles et caractérisation

    OpenAIRE

    Jurkiewiez B.; Si Larbi A.; Hamelin P.

    2011-01-01

    Nous présentons les résultats d’une étude sur des mortiers renforcés de fibres de lin. Une brève étude bibliographique montre notamment que le lin en tant que renfort a fait l’objet de peu de travaux malgré une disponibilité importante, un coût peu élevé et de bonnes propriétés spécifiques. Nous montrons ensuite que, du point de vue de la mise en oeuvre et du comportement mécanique, les conditionnements de la fibre de lin sous forme de fibres courtes ou de grilles apparaisse...

  6. Lin28A induces energetic switching to glycolytic metabolism in human embryonic kidney cells.

    Science.gov (United States)

    Docherty, Craig K; Salt, Ian P; Mercer, John R

    2016-05-26

    Loss of a cell's capacity to generate sufficient energy for cellular functions is a key hallmark of the ageing process and ultimately leads to a variety of important age-related pathologies such as cancer, Parkinson's disease and atherosclerosis. Regenerative medicine has sought to reverse these pathologies by reprogramming somatic cells to a more juvenile energetic state using a variety of stem cell factors. One of these factors, Lin28, is considered a candidate for modification in the reprogramming of cellular energetics to ameliorate the ageing process while retaining cell phenotype. Over-expression of Lin28A resulted in key changes to cellular metabolism not observed in wild-type controls. Extracellular pH flux analysis indicated that Lin28A over expression significantly increased the rate of glycolysis, whilst high resolution oxygen respirometry demonstrated a reduced oxygen consumption. Western blot and real-time PCR analysis identified Hexokinase II as one of the key modulators of glycolysis in these cells which was further confirmed by increased glucose transport. A metabolic switching effect was further emphasised by Western blot analysis where the oxygen consuming mitochondrial complex IV was significantly reduced after Lin28A over expression. Results from this study confirm that Lin28A expression promotes metabolic switching to a phenotype that relies predominantly on glycolysis as an energy source, while compromising oxidative phosphorylation. Mechanisms to augment regulated Lin28A in age related pathologies that are characterised by mitochondria dysfunction or in differentiated and aged post-mitotic cells is the future goal of this work.

  7. Mechanism of Dis3l2 substrate recognition in the Lin28-let-7 pathway.

    Science.gov (United States)

    Faehnle, Christopher R; Walleshauser, Jack; Joshua-Tor, Leemor

    2014-10-09

    The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Overexpression of Lin28 is correlated with the onset of numerous cancers, whereas let-7, a tumour suppressor, silences several human oncogenes. Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3' oligo-uridylation activity of TUT4 and TUT7 (refs 10-12). The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by Dis3l2 (refs 13, 14), a homologue of the catalytic subunit of the RNA exosome. The molecular basis of Lin28-mediated recruitment of TUT4 and TUT7 to pre-let-7 and its subsequent degradation by Dis3l2 is largely unknown. To examine the mechanism of Dis3l2 substrate recognition we determined the structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let-7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. We identify three U-specificity zones that explain how Dis3l2 recognizes, binds and processes uridylated pre-let-7 in the final step of the Lin28-let-7 pathway.

  8. The Lin28/Let-7 system in early human embryonic tissue and ectopic pregnancy.

    Directory of Open Access Journals (Sweden)

    Teresa Lozoya

    Full Text Available Our objective was to determine the expression of the elements of the Lin28/Let-7 system, and related microRNAs (miRNAs, in early stages of human placentation and ectopic pregnancy, as a means to assess the potential role of this molecular hub in the pathogenesis of ectopic gestation. Seventeen patients suffering from tubal ectopic pregnancy (cases and forty-three women with normal on-going gestation that desired voluntary termination of pregnancy (VTOP; controls were recruited for the study. Embryonic tissues were subjected to RNA extraction and quantitative PCR analyses for LIN28B, Let-7a, miR-132, miR-145 and mir-323-3p were performed. Our results demonstrate that the expression of LIN28B mRNA was barely detectable in embryonic tissue from early stages of gestation and sharply increased thereafter to plateau between gestational weeks 7-9. In contrast, expression levels of Let-7, mir-132 and mir-145 were high in embryonic tissue from early gestations (≤ 6-weeks and abruptly declined thereafter, especially for Let-7. Opposite trends were detected for mir-323-3p. Embryonic expression of LIN28B mRNA was higher in early stages (≤ 6-weeks of ectopic pregnancy than in normal gestation. In contrast, Let-7a expression was significantly lower in early ectopic pregnancies, while miR-132 and miR-145 levels were not altered. Expression of mir-323-3p was also suppressed in ectopic embryonic tissue. We are the first to document reciprocal changes in the expression profiles of the gene encoding the RNA-binding protein, LIN28B, and the related miRNAs, Let-7a, mir-132 and mir-145, in early stages of human placentation. This finding suggests the potential involvement of LIN28B/Let-7 (deregulated pathways in the pathophysiology of ectopic pregnancy in humans.

  9. LIN28 Expression in malignant germ cell tumors downregulates let-7 and increases oncogene levels.

    Science.gov (United States)

    Murray, Matthew J; Saini, Harpreet K; Siegler, Charlotte A; Hanning, Jennifer E; Barker, Emily M; van Dongen, Stijn; Ward, Dawn M; Raby, Katie L; Groves, Ian J; Scarpini, Cinzia G; Pett, Mark R; Thornton, Claire M; Enright, Anton J; Nicholson, James C; Coleman, Nicholas

    2013-08-01

    Despite their clinicopathologic heterogeneity, malignant germ cell tumors (GCT) share molecular abnormalities that are likely to be functionally important. In this study, we investigated the potential significance of downregulation of the let-7 family of tumor suppressor microRNAs in malignant GCTs. Microarray results from pediatric and adult samples (n = 45) showed that LIN28, the negative regulator of let-7 biogenesis, was abundant in malignant GCTs, regardless of patient age, tumor site, or histologic subtype. Indeed, a strong negative correlation existed between LIN28 and let-7 levels in specimens with matched datasets. Low let-7 levels were biologically significant, as the sequence complementary to the 2 to 7 nt common let-7 seed "GAGGUA" was enriched in the 3' untranslated regions of mRNAs upregulated in pediatric and adult malignant GCTs, compared with normal gonads (a mixture of germ cells and somatic cells). We identified 27 mRNA targets of let-7 that were upregulated in malignant GCT cells, confirming significant negative correlations with let-7 levels. Among 16 mRNAs examined in a largely independent set of specimens by quantitative reverse transcription PCR, we defined negative-associations with let-7e levels for six oncogenes, including MYCN, AURKB, CCNF, RRM2, MKI67, and C12orf5 (when including normal control tissues). Importantly, LIN28 depletion in malignant GCT cells restored let-7 levels and repressed all of these oncogenic let-7 mRNA targets, with LIN28 levels correlating with cell proliferation and MYCN levels. Conversely, ectopic expression of let-7e was sufficient to reduce proliferation and downregulate MYCN, AURKB, and LIN28, the latter via a double-negative feedback loop. We conclude that the LIN28/let-7 pathway has a critical pathobiologic role in malignant GCTs and therefore offers a promising target for therapeutic intervention. ©2013 AACR.

  10. The Lin28/Let-7 system in early human embryonic tissue and ectopic pregnancy.

    Science.gov (United States)

    Lozoya, Teresa; Domínguez, Francisco; Romero-Ruiz, Antonio; Steffani, Liliana; Martínez, Sebastián; Monterde, Mercedes; Ferri, Blanca; Núñez, Maria Jose; AinhoaRomero-Espinós; Zamora, Omar; Gurrea, Marta; Sangiao-Alvarellos, Susana; Vega, Olivia; Simón, Carlos; Pellicer, Antonio; Tena-Sempere, Manuel

    2014-01-01

    Our objective was to determine the expression of the elements of the Lin28/Let-7 system, and related microRNAs (miRNAs), in early stages of human placentation and ectopic pregnancy, as a means to assess the potential role of this molecular hub in the pathogenesis of ectopic gestation. Seventeen patients suffering from tubal ectopic pregnancy (cases) and forty-three women with normal on-going gestation that desired voluntary termination of pregnancy (VTOP; controls) were recruited for the study. Embryonic tissues were subjected to RNA extraction and quantitative PCR analyses for LIN28B, Let-7a, miR-132, miR-145 and mir-323-3p were performed. Our results demonstrate that the expression of LIN28B mRNA was barely detectable in embryonic tissue from early stages of gestation and sharply increased thereafter to plateau between gestational weeks 7-9. In contrast, expression levels of Let-7, mir-132 and mir-145 were high in embryonic tissue from early gestations (≤ 6-weeks) and abruptly declined thereafter, especially for Let-7. Opposite trends were detected for mir-323-3p. Embryonic expression of LIN28B mRNA was higher in early stages (≤ 6-weeks) of ectopic pregnancy than in normal gestation. In contrast, Let-7a expression was significantly lower in early ectopic pregnancies, while miR-132 and miR-145 levels were not altered. Expression of mir-323-3p was also suppressed in ectopic embryonic tissue. We are the first to document reciprocal changes in the expression profiles of the gene encoding the RNA-binding protein, LIN28B, and the related miRNAs, Let-7a, mir-132 and mir-145, in early stages of human placentation. This finding suggests the potential involvement of LIN28B/Let-7 (de)regulated pathways in the pathophysiology of ectopic pregnancy in humans.

  11. Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6.

    Science.gov (United States)

    Liu, Wan-Ju; Reece-Hoyes, John S; Walhout, Albertha J M; Eisenmann, David M

    2014-05-13

    Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo. We used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs. These results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a

  12. [Professor LIN Guohua's experience of gold implantation at acupoint for rheumatoid arthritis].

    Science.gov (United States)

    Li, Jingjing; Pei, Wenya

    2015-12-01

    Based on the pathogenesis and symptom of rheumatoid arthritis (RA), professor LIN Guohua's unique opinion and method for RA in clinical treatment are summarized and analyzed. In the opinion of Professor Lin, RA is considered as "Jinbi" and "Gubi" in TCM, which is caused by deficient root with superficial excess. Based on the symptoms of RA, attention should be focused on lung-kidney diagnosis and treatment, and gold and catgut implantation at acupoint can be mutually combined, which is aimed to provide a special and effective method for clinical treatment of RA.

  13. Lin28 induces epithelial-to-mesenchymal transition and stemness via downregulation of let-7a in breast cancer cells.

    Science.gov (United States)

    Liu, Yujie; Li, Haiyan; Feng, Juan; Cui, Xiuying; Huang, Wei; Li, Yudong; Su, Fengxi; Liu, Qiang; Zhu, Jiujun; Lv, Xiaobin; Chen, Jianing; Huang, Di; Yu, Fengyan

    2013-01-01

    The RNA-binding protein Lin28 is known to promote malignancy by inhibiting the biogenesis of let-7, which functions as a tumor suppressor. However, the role of the Lin28/let-7 axis in the epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer has not been clearly expatiated. In our previous study, we demonstrated that let-7 regulates self-renewal and tumorigenicity of breast cancer stem cells. In the present study, we demonstrated that Lin28 was highly expressed in mesenchymal (M) type cells (MDA-MB-231 and SK-3rd), but it was barely detectable in epithelial (E) type cells (MCF-7 and BT-474). Lin28 remarkably induced the EMT, increased a higher mammosphere formation rate and ALDH activity and subsequently promoted colony formation, as well as adhesion and migration in breast cancer cells. Furthermore, we demonstrated that Lin28 induced EMT in breast cancer cells via downregulation of let-7a. Strikingly, Lin28 overexpression was found in breast cancers that had undergone metastasis and was strongly predictive of poor prognoses in breast cancers. Given that Lin28 induced the EMT via let-7a and promoted breast cancer metastasis, Lin28 may be a therapeutic target for the eradication of breast cancer metastasis.

  14. Lin28 induces epithelial-to-mesenchymal transition and stemness via downregulation of let-7a in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yujie Liu

    Full Text Available The RNA-binding protein Lin28 is known to promote malignancy by inhibiting the biogenesis of let-7, which functions as a tumor suppressor. However, the role of the Lin28/let-7 axis in the epithelial-to-mesenchymal transition (EMT and stemness in breast cancer has not been clearly expatiated. In our previous study, we demonstrated that let-7 regulates self-renewal and tumorigenicity of breast cancer stem cells. In the present study, we demonstrated that Lin28 was highly expressed in mesenchymal (M type cells (MDA-MB-231 and SK-3rd, but it was barely detectable in epithelial (E type cells (MCF-7 and BT-474. Lin28 remarkably induced the EMT, increased a higher mammosphere formation rate and ALDH activity and subsequently promoted colony formation, as well as adhesion and migration in breast cancer cells. Furthermore, we demonstrated that Lin28 induced EMT in breast cancer cells via downregulation of let-7a. Strikingly, Lin28 overexpression was found in breast cancers that had undergone metastasis and was strongly predictive of poor prognoses in breast cancers. Given that Lin28 induced the EMT via let-7a and promoted breast cancer metastasis, Lin28 may be a therapeutic target for the eradication of breast cancer metastasis.

  15. Kinetic and sequence-structure-function analysis of known LinA variants with different hexachlorocyclohexane isomers.

    Directory of Open Access Journals (Sweden)

    Pooja Sharma

    Full Text Available BACKGROUND: Here we report specific activities of all seven naturally occurring LinA variants towards three different isomers, α, γ and δ, of a priority persistent pollutant, hexachlorocyclohexane (HCH. Sequence-structure-function differences contributing to the differences in their stereospecificity for α-, γ-, and δ-HCH and enantiospecificity for (+- and (--α -HCH are also discussed. METHODOLOGY/PRINCIPAL FINDINGS: Enzyme kinetic studies were performed with purified LinA variants. Models of LinA2(B90A A110T, A111C, A110T/A111C and LinA1(B90A were constructed using the FoldX computer algorithm. Turnover rates (min(-1 showed that the LinAs exhibited differential substrate affinity amongst the four HCH isomers tested. α-HCH was found to be the most preferred substrate by all LinA's, followed by the γ and then δ isomer. CONCLUSIONS/SIGNIFICANCE: The kinetic observations suggest that LinA-γ1-7 is the best variant for developing an enzyme-based bioremediation technology for HCH. The majority of the sequence variation in the various linA genes that have been isolated is not neutral, but alters the enantio- and stereoselectivity of the encoded proteins.

  16. Symmetry group theorem to the Lin-Tsien equation and conservation laws relating to the symmetry of the equation?

    OpenAIRE

    Xi-Zhong, Liu

    2012-01-01

    In this paper, We derive the symmetry group theorem to the Lin-Tsien equation by using the modified CK's direct method, from which we obtain the corresponding symmetry group. More importantly, conservation laws corresponding to the Kac-Moody-Virasoro symmetry algebra of Lin-Tsien equation is obtained up to second order group invariants.

  17. Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Kezhen Lv

    Full Text Available Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer.

  18. Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells.

    Science.gov (United States)

    Lv, Kezhen; Liu, Liqun; Wang, Linbo; Yu, Jiren; Liu, Xiaojiao; Cheng, Yongxia; Dong, Minjun; Teng, Rongyue; Wu, Linjiao; Fu, Peifen; Deng, Wuguo; Hu, Wenxian; Teng, Lisong

    2012-01-01

    Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer.

  19. The ubiquitin ligase human TRIM71 regulates let-7 microRNA biogenesis via modulation of Lin28B protein.

    Science.gov (United States)

    Lee, Seo Hyun; Cho, Sungchan; Kim, M Sun; Choi, Kwangman; Cho, Jae Youl; Gwak, Ho-Shin; Kim, Youn-Jae; Yoo, Heon; Lee, Seung-Hoon; Park, Jong Bae; Kim, Jong Heon

    2014-05-01

    let-7 microRNA (miRNA) is implicated in various biological processes, and its downregulation essentially linked to human malignancy. Regulation of gene expression of the let-7 family is critically linked to RNA-binding proteins. For instance, Lin28B and its paralog, Lin28A, inhibit the pre-let-7 precursor from being processed to mature miRNA by recruiting terminal uridyltransferase, TUT4, which adds oligomeric U at the 3' end, suggesting that deregulation of Lin28B, together with Lin28A, may alter various biological processes through modulation of let-7 expression. Here, we showed that the Lin28B protein level is regulated via ubiquitin-mediated proteasomal degradation, and identified the ubiquitin ligase as human TRIM-NHL domain-containing TRIM71. In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination. Compared with its paralog, Lin28A, a C-terminal unique ~50 amino acid stretch of Lin28B is essential for TRIM71 interactions and subsequent polyubiquitination. Moreover, the N-terminal RING finger motif of TRIM71 is critical for protein-protein interactions and polyubiquitination of Lin28B, and consequent let-7 expression. Consistent with the let-7 stimulatory role of TRIM71 via Lin28B polyubiquitination, specific knockdown of TRIM71 led to downregulation of let-7 expression. Expression of one of the known let-7 targets, HMGA2, was derepressed after knockdown of TRIM71. We additionally showed that enhanced expression of let-7 is part of a feedback loop that targets TRIM71 3'UTR, which contains two conserved let-7 target sites. Our findings collectively reveal critical aspects of regulatory complexity of let-7 biogenesis at the posttranscriptional level. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation.

    Science.gov (United States)

    Liu, Xiangyuan; Chen, Min; Li, Long; Gong, Liyan; Zhou, Hu; Gao, Daming

    2017-03-10

    Lin28a, originally discovered in the nematode Caenorhabditis elegans and highly conserved across species, is a well characterized regulator of let-7 microRNA (miRNA) and is implicated in cell proliferation and pluripotency control. However, little is known about how Lin28a function is modulated at the post-translational level and thereby responds to major signaling pathways. Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200. By editing lin28a gene with the CRISPR/Cas9-based method, we generated P19 mouse embryonic carcinoma stem cells expressing Lin28a-S200A (phospho-deficient) and Lin28a-S200D (phospho-mimetic) mutants, respectively, to study the functional impact of Ser-200 phosphorylation. Lin28a-S200D-expressing cells, but not Lin28a-S200A-expressing or control P19 embryonic carcinoma cells, displayed impaired inhibition of let-7 miRNA and resulted in decreased cyclin D1, whereas Lin28a-S200A knock-in cells expressed less let-7 miRNA, proliferated faster, and exhibited differentiation defect upon retinoic acid induction. Therefore our results support that ERK kinase-mediated Lin28a phosphorylation may be an important mechanism for pluripotent cells to facilitate the escape from the self-renewal cycle and start the differentiation process. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Expression of exogenous LIN28 contributes to proliferation and survival of mouse primary cortical neurons in vitro.

    Science.gov (United States)

    Bhuiyan, M I H; Lee, J-H; Kim, S Y; Cho, K-O

    2013-09-17

    LIN28, an RNA-binding protein, is known to be involved in the regulation of many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. In this study, we investigated the effect of constitutively expressing exogenous LIN28 on neuronal cell proliferation and viability in vitro. Plasmids containing LIN28-green fluorescent protein (GFP) or GFP were introduced into the embryonic mouse brains at E14.5 by in utero electroporation. Two days after electroporation, embryonic cortices were harvested and cultured. It was found that transfected cells stably overexpressed LIN28 in vitro. Viability curve from live cell imaging showed that the number of GFP-expressing cells decreased over time in line with naive primary cortical neurons. In contrast, the number of LIN28-GFP-overexpressing neurons initially increased and remained high at later time-points in culture than GFP-expressing cells. Double immunofluorescence showed that at an early time in culture, the number of Ki-67/GFP double-positive cells was higher in the LIN28-GFP group than that of controls. Moreover, there were significantly lower numbers of condensed nuclei/GFP- and cleaved caspase-3/GFP-positive cells in the LIN28-GFP groups compared to control GFP. Furthermore, it was confirmed that the LIN28-GFP-expressing cells at days in vitro (DIV)13 were neuronal nuclei (NeuN)-positive mature neurons. Finally, the expression of insulin-like growth factor 2 (IGF-2) was induced in LIN28-expressing primary cortical neurons, which was not detected in controls. Taken together, our results indicate that the expression of exogenous LIN28 can promote the proliferation of neural progenitor cells and exert prosurvival effect on primary cortical neurons by inhibiting caspase-dependent apoptosis, possibly via upregulation of IGF-2. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Identification of residues of the Caenorhabditis elegans LIN-1 ETS domain that are necessary for DNA binding and regulation of vulval cell fates.

    Science.gov (United States)

    Miley, Ginger R; Fantz, Douglas; Glossip, Danielle; Lu, Xiaowei; Saito, R Mako; Palmer, Robert E; Inoue, Takao; Van Den Heuvel, Sander; Sternberg, Paul W; Kornfeld, Kerry

    2004-08-01

    LIN-1 is an ETS domain protein. A receptor tyrosine kinase/Ras/mitogen-activated protein kinase signaling pathway regulates LIN-1 in the P6.p cell to induce the primary vulval cell fate during Caenorhabditis elegans development. We identified 23 lin-1 loss-of-function mutations by conducting several genetic screens. We characterized the molecular lesions in these lin-1 alleles and in several previously identified lin-1 alleles. Nine missense mutations and 10 nonsense mutations were identified. All of these lin-1 missense mutations affect highly conserved residues in the ETS domain. These missense mutations can be arranged in an allelic series; the strongest mutations eliminate most or all lin-1 functions, and the weakest mutation partially reduces lin-1 function. An electrophoretic mobility shift assay was used to demonstrate that purified LIN-1 protein has sequence-specific DNA-binding activity that required the core sequence GGAA. LIN-1 mutant proteins containing the missense substitutions had dramatically reduced DNA binding. These experiments identify eight highly conserved residues of the ETS domain that are necessary for DNA binding. The identification of multiple mutations that reduce the function of lin-1 as an inhibitor of the primary vulval cell fate and also reduce DNA binding suggest that DNA binding is essential for LIN-1 function in an animal.

  3. New explicit and exact solutions of the Benney-Kawahara-Lin equation

    Institute of Scientific and Technical Information of China (English)

    Xie Yuan-Xi

    2009-01-01

    In this paper, we present a combination method of constructing the explicit and exact solutions of nonlinear partial differential equations. And as an illustrative example, we apply the method to the Benney-Kawahara-Lin equation and derive its many explicit and exact solutions which are all new solutions.

  4. LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation

    Directory of Open Access Journals (Sweden)

    Longfei Wang

    2017-03-01

    Full Text Available LIN28 is an RNA binding protein that plays crucial roles in pluripotency, glucose metabolism, tissue regeneration, and tumorigenesis. LIN28 binds to the let-7 primary and precursor microRNAs through bipartite recognition and induces degradation of let-7 precursors (pre-let-7 by promoting oligouridylation by terminal uridylyltransferases (TUTases. Here, we report that the zinc knuckle domain (ZKD of mouse LIN28 recruits TUT4 to initiate the oligouridylation of let-7 precursors. Our crystal structure of human LIN28 in complex with a fragment of pre-let-7f-1 determined to 2.0 Å resolution shows that the interaction between ZKD and RNA is constrained to a small cavity with a high druggability score. We demonstrate that the specific interaction between ZKD and pre-let-7 is necessary and sufficient to induce oligouridylation by recruiting the N-terminal fragment of TUT4 (NTUT4 and the formation of a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for the acquired processivity of TUT4.

  5. LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation.

    Science.gov (United States)

    Wang, Longfei; Nam, Yunsun; Lee, Anna K; Yu, Chunxiao; Roth, Kira; Chen, Casandra; Ransey, Elizabeth M; Sliz, Piotr

    2017-03-14

    LIN28 is an RNA binding protein that plays crucial roles in pluripotency, glucose metabolism, tissue regeneration, and tumorigenesis. LIN28 binds to the let-7 primary and precursor microRNAs through bipartite recognition and induces degradation of let-7 precursors (pre-let-7) by promoting oligouridylation by terminal uridylyltransferases (TUTases). Here, we report that the zinc knuckle domain (ZKD) of mouse LIN28 recruits TUT4 to initiate the oligouridylation of let-7 precursors. Our crystal structure of human LIN28 in complex with a fragment of pre-let-7f-1 determined to 2.0 Å resolution shows that the interaction between ZKD and RNA is constrained to a small cavity with a high druggability score. We demonstrate that the specific interaction between ZKD and pre-let-7 is necessary and sufficient to induce oligouridylation by recruiting the N-terminal fragment of TUT4 (NTUT4) and the formation of a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for the acquired processivity of TUT4. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Lin28a regulates neuronal differentiation and controls miR-9 production.

    Science.gov (United States)

    Nowak, Jakub S; Choudhury, Nila Roy; de Lima Alves, Flavia; Rappsilber, Juri; Michlewski, Gracjan

    2014-04-11

    microRNAs shape the identity and function of cells by regulating gene expression. It is known that brain-specific miR-9 is controlled transcriptionally; however, it is unknown whether post-transcriptional processes contribute to establishing its levels. Here we show that miR-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation of the embryonic carcinoma cell line P19. We demonstrate that miR-9 is more efficiently processed in differentiated than in undifferentiated cells. We reveal that Lin28a affects miR-9 by inducing the degradation of its precursor through a uridylation-independent mechanism. Furthermore, we show that constitutively expressed untagged but not GFP-tagged Lin28a decreases differentiation capacity of P19 cells, which coincides with reduced miR-9 levels. Finally, using an inducible system we demonstrate that Lin28a can also reduce miR-9 levels in differentiated P19 cells. Together, our results shed light on the role of Lin28a in neuronal differentiation and increase our understanding of the mechanisms regulating the level of brain-specific microRNAs.

  7. Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment

    Science.gov (United States)

    Ma, Wei; Ma, Jing; Xu, Jie; Qiao, Chong; Branscum, Adam; Cardenas, Andres; Baron, Andre T.; Schwartz, Peter; Maihle, Nita J.; Huang, Yingqun

    2013-01-01

    Emerging evidence suggests that the tumor microenvironment plays a critical role in regulating cancer stem cells (CSCs) and tumor progression through both autocrine and paracrine signaling. Elevated production of bone morphogenetic proteins (BMPs) from human ovarian cancer cells and stroma has been shown to increase CSC proliferation and tumor growth. Here, we report that Lin28, a stem cell factor, binds to BMP4 mRNA in epithelial ovarian carcinoma cells, thereby promoting BMP4 expression at the post-transcriptional level. As co-expression of Lin28 and Oct4 (another stem cell factor) has been implicated in ovarian cancer CSCs, we also determined that high levels of Lin28 are associated with an unfavorable prognosis when co-expressed with high levels of Oct4. Together, these findings uncover a new level of regulation of BMP4 expression and imply a novel Lin28/Oct4/BMP4-mediated mechanism of regulating ovarian tumor cell growth, thus holding potential for the development of new strategies for the diagnosis and treatment of ovarian cancer. PMID:23255092

  8. The Value of SCMC in SLA: Comments on Lin, Huang & Liou (2013)

    Science.gov (United States)

    Taylor, Alan M.

    2014-01-01

    Meta-analytic methods are often used to determine the effectiveness of certain treatments across studies. However, we are often unaware of how a meta-analysis can provide value to researchers and practitioners. This paper offers a brief commentary on a meta-analysis conducted by Lin, Huang and Liou (2013) in LLT, providing further statistical…

  9. An Effective Implementation of K-opt Moves for the Lin-Kernighan TSP Heuristic

    DEFF Research Database (Denmark)

    Helsgaun, Keld

    Local search with k-change neighborhoods, k-opt, is the most widely used heuristic method for the traveling salesman problem (TSP). This report presents an effective implementation of k-opt for the Lin- Kernighan TSP heuristic. The effectiveness of the implementation is demonstrated with extensive...

  10. Cryptanalysis of Lin et al.'s Efficient Block-Cipher-Based Hash Function

    NARCIS (Netherlands)

    Liu, Bozhong; Gong, Zheng; Chen, Xiaohong; Qiu, Weidong; Zheng, Dong

    2010-01-01

    Hash functions are widely used in authentication. In this paper, the security of Lin et al.'s efficient block-cipher-based hash function is reviewed. By using Joux's multicollisions and Kelsey et al.'s expandable message techniques, we find the scheme is vulnerable to collision, preimage and second

  11. The Value of SCMC in SLA: Comments on Lin, Huang & Liou (2013)

    Science.gov (United States)

    Taylor, Alan M.

    2014-01-01

    Meta-analytic methods are often used to determine the effectiveness of certain treatments across studies. However, we are often unaware of how a meta-analysis can provide value to researchers and practitioners. This paper offers a brief commentary on a meta-analysis conducted by Lin, Huang and Liou (2013) in LLT, providing further statistical…

  12. linäituse stendid = Outdoor exhibition stands / Gert Sarv, Galina Burnakova

    Index Scriptorium Estoniae

    Sarv, Gert, 1971-

    2013-01-01

    Eesti Sisearhitektide Liidu 2012. aasta parima eseme preemia pälvinud välinäituse stendidest Vanasadama Admiraliteedi basseini kaldapealsel. Autorid: Gert Sarv, Galina Burnakova, Loreida Hein. Sisearhitekti ja ESLi aastapreemiate žürii liikme Tea Tammelaane arvamus

  13. Single-tube linear DNA amplification (LinDA) for robust ChIP-seq

    NARCIS (Netherlands)

    Shankaranarayanan, P.; Mendoza-Parra, M.A.; Walia, M.; Wang, L.; Li, N.; Trindade, L.M.; Gronemeyer, H.

    2011-01-01

    Genome-wide profiling of transcription factors based on massive parallel sequencing of immunoprecipitated chromatin (ChIP-seq) requires nanogram amounts of DNA. Here we describe a high-fidelity, single-tube linear DNA amplification method (LinDA) for ChIP-seq and reChIP-seq with picogram DNA amounts

  14. linäituse stendid = Outdoor exhibition stands / Gert Sarv, Galina Burnakova

    Index Scriptorium Estoniae

    Sarv, Gert, 1971-

    2013-01-01

    Eesti Sisearhitektide Liidu 2012. aasta parima eseme preemia pälvinud välinäituse stendidest Vanasadama Admiraliteedi basseini kaldapealsel. Autorid: Gert Sarv, Galina Burnakova, Loreida Hein. Sisearhitekti ja ESLi aastapreemiate žürii liikme Tea Tammelaane arvamus

  15. Polyamines are oncometabolites that regulate the LIN28/let-7 pathway in colorectal cancer cells.

    Science.gov (United States)

    Paz, Edwin A; LaFleur, Bonnie; Gerner, Eugene W

    2014-02-01

    Polyamine metabolism is a highly coordinated process that is essential for normal development and neoplastic growth in mammals. Although polyamine metabolism is a validated pathway for prevention of carcinogenesis, the mechanisms by which polyamines elicit their tumorigenic effects are poorly understood. In this study, we investigated the role of polyamine metabolism in colon cancer by screening a non-coding RNA (ncRNA) platform to identify polyamine responsive signaling nodes. We report that multiple non-coding RNAs are altered by polyamine depletion including induction of microRNA (miRNA) let-7i, a member of the tumor suppressive let-7 family. The let-7 family targets several RNAs for translational repression, including the growth-associated transcription factor HMGA2 and is negatively regulated by the pluripotency factor LIN28. Depletion of polyamines using difluoromethylornithine (DFMO) or genetic knockdown of the polyamine-modified eukaryotic translation initiation factor 5A isoforms 1 and 2 (eIF5A1/2) resulted in robust reduction of both HMGA2 and LIN28. Locked nucleic acid (LNA) oligonucleotides targeting the seed region of the let-7 family rescued the expression of HMGA2, but not LIN28, in both DFMO-treated and eIF5A1/2 knockdown cultures. Our findings suggest that polyamines are oncometabolites that influence specific aspects of tumorigenesis by regulating pluripotency associated factors, such as LIN28, via an eIF5A-dependent but let-7-independent mechanism while the expression of proliferation-related genes regulated by let-7, such as HMGA2, is mediated through microRNA mediated repression. Therefore, manipulating polyamine metabolism may be a novel method of targeting the LIN28/let-7 pathway in specific disease states. © 2013 Wiley Periodicals, Inc.

  16. Aire Promotes the Self-Renewal of Embryonic Stem Cells Through Lin28

    Science.gov (United States)

    Bin, Gu; Jiarong, Zhang; Shihao, Wang; Xiuli, Song; Cheng, Xu

    2012-01-01

    Abstract Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. In this study, we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells. We presented the first evidence that the let-7 microRNA family contributed to the self-renewal promoting effect of Aire on ES cells. Moreover, we showed that Aire and Lin28 are co-expressed in the genital ridge, oocytes, and cleavage-stage embryos, and the expression level of Lin28 is correlated with the expression level of Aire. Although it is widely considered to be a promiscuous gene expression activator, these results indicated that Aire promotes the self-renewal of ES cells through a specific pathway (i.e., the activation of Lin28 and the inhibition of the let-7 microRNA family). The correlation between Aire and Lin28 expression in germ cells and early embryos indicated an in vivo function for Aire in toti- and pluripotent stem cells. This study presents the first molecular pathway that incorporates Aire into the pluripotency network. Moreover, it presents the first evidence that microRNAs contribute to the regulatory function of Aire and highlights a novel function of Aire in stem cell biology and reproduction. These functions reveal novel perspectives for studying the molecular mechanisms behind the establishment and sustenance of pluripotent identity. PMID:22540148

  17. Aire promotes the self-renewal of embryonic stem cells through Lin28.

    Science.gov (United States)

    Bin, Gu; Jiarong, Zhang; Shihao, Wang; Xiuli, Song; Cheng, Xu; Liangbiao, Chen; Ming, Zhang

    2012-10-10

    Abstract Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. In this study, we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells. We presented the first evidence that the let-7 microRNA family contributed to the self-renewal promoting effect of Aire on ES cells. Moreover, we showed that Aire and Lin28 are co-expressed in the genital ridge, oocytes, and cleavage-stage embryos, and the expression level of Lin28 is correlated with the expression level of Aire. Although it is widely considered to be a promiscuous gene expression activator, these results indicated that Aire promotes the self-renewal of ES cells through a specific pathway (i.e., the activation of Lin28 and the inhibition of the let-7 microRNA family). The correlation between Aire and Lin28 expression in germ cells and early embryos indicated an in vivo function for Aire in toti- and pluripotent stem cells. This study presents the first molecular pathway that incorporates Aire into the pluripotency network. Moreover, it presents the first evidence that microRNAs contribute to the regulatory function of Aire and highlights a novel function of Aire in stem cell biology and reproduction. These functions reveal novel perspectives for studying the molecular mechanisms behind the establishment and sustenance of pluripotent identity.

  18. Lin-28 homologue A (LIN28A) promotes cell cycle progression via regulation of cyclin-dependent kinase 2 (CDK2), cyclin D1 (CCND1), and cell division cycle 25 homolog A (CDC25A) expression in cancer.

    Science.gov (United States)

    Li, Ning; Zhong, Xiaomin; Lin, Xiaojuan; Guo, Jinyi; Zou, Lian; Tanyi, Janos L; Shao, Zhongjun; Liang, Shun; Wang, Li-Ping; Hwang, Wei-Ting; Katsaros, Dionyssios; Montone, Kathleen; Zhao, Xia; Zhang, Lin

    2012-05-18

    The RNA-binding protein LIN28A regulates the translation and stability of a large number of mRNAs as well as the biogenesis of certain miRNAs in embryonic stem cells and developing tissues. Increasing evidence indicates that LIN28A functions as an oncogene promoting cancer cell growth. However, little is known about its molecular mechanism of cell cycle regulation in cancer. Using tissue microarrays, we found that strong LIN28A expression was reactivated in about 10% (7.1-17.1%) of epithelial tumors (six tumor types, n = 369). Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Genome-wide RNA-IP-chip experiments indicate that LIN28A binds to thousands of mRNAs, including a large group of cell cycle regulatory mRNAs in cancer and embryonic stem cells. Furthermore, the ability of LIN28A to stimulate translation of LIN28A-binding mRNAs, such as CDK2, was validated in vitro and in vivo. Finally, using a combined gene expression microarray and bioinformatics approach, we found that LIN28A also regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA. Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent).

  19. Lin-28 Homologue A (LIN28A) Promotes Cell Cycle Progression via Regulation of Cyclin-dependent Kinase 2 (CDK2), Cyclin D1 (CCND1), and Cell Division Cycle 25 Homolog A (CDC25A) Expression in Cancer*

    Science.gov (United States)

    Li, Ning; Zhong, Xiaomin; Lin, Xiaojuan; Guo, Jinyi; Zou, Lian; Tanyi, Janos L.; Shao, Zhongjun; Liang, Shun; Wang, Li-Ping; Hwang, Wei-Ting; Katsaros, Dionyssios; Montone, Kathleen; Zhao, Xia; Zhang, Lin

    2012-01-01

    The RNA-binding protein LIN28A regulates the translation and stability of a large number of mRNAs as well as the biogenesis of certain miRNAs in embryonic stem cells and developing tissues. Increasing evidence indicates that LIN28A functions as an oncogene promoting cancer cell growth. However, little is known about its molecular mechanism of cell cycle regulation in cancer. Using tissue microarrays, we found that strong LIN28A expression was reactivated in about 10% (7.1–17.1%) of epithelial tumors (six tumor types, n = 369). Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Genome-wide RNA-IP-chip experiments indicate that LIN28A binds to thousands of mRNAs, including a large group of cell cycle regulatory mRNAs in cancer and embryonic stem cells. Furthermore, the ability of LIN28A to stimulate translation of LIN28A-binding mRNAs, such as CDK2, was validated in vitro and in vivo. Finally, using a combined gene expression microarray and bioinformatics approach, we found that LIN28A also regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA. Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent). PMID:22467868

  20. Does Lin28 Antagonize miRNA-Mediated Repression by Displacing miRISC from Target mRNAs?

    Science.gov (United States)

    Kallen, Amanda N; Ma, Jing; Huang, Yingqun

    2012-01-01

    Lin28 is a developmentally regulated RNA-binding protein that plays important roles in diverse physiological and pathological processes including oncogenesis and brain synaptic function. These pleiotropic roles of Lin28 are mechanistically linked both to its ability to directly stimulate translation of genes involved primarily in cell growth and metabolism and to its ability to block biogenesis of a subset of miRNAs including the let-7 family of miRNAs. In the case of direct stimulation of gene expression, Lin28 binds to targeted mRNAs through recognition of Lin28-responsive elements (LREs) within mRNAs and recruits RNA helicase A (RHA) to promote translation. RHA belongs to the DEAD-box protein family of RNA helicases, which generally catalyze ATP-dependent unwinding of RNA duplexes or remodeling of ribonucleoprotein complexes (RNPs). Since any given mRNA can potentially be inhibited by miRNAs bearing complementary sequences, we hypothesize that binding of Lin28 to LREs not only nucleates the binding of multiple Lin28 molecules to the same mRNA, but also leads to remodeling of RNPs through recruitment of RHA and causes release of inhibitory miRNA-induced silencing complexes bound to the mRNA. This mode of action may contribute to Lin28-mediated stimulation of translation in both tumor and neuronal cells.

  1. Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing.

    Science.gov (United States)

    Lightfoot, Helen L; Miska, Eric A; Balasubramanian, Shankar

    2016-11-02

    The protein Lin28 and microRNA let-7 play critical roles in mammalian development and human disease. Lin28 inhibits let-7 biogenesis through direct interaction with let-7 precursors (pre-let-7). Accumulating evidence in vitro and in vivo suggests this interaction plays a dominant role in embryonic stem cell self-renewal and tumorigenesis. Thus the Lin28-let-7 interaction might be an attractive drug target, if not for the well-known difficulties in targeting protein-RNA interactions with drugs. The identification and development of suitable probe molecules to further elucidate therapeutic potential, as well as mechanistic details of this pathway will be valuable. We report the development and application of a biophysical high-throughput screening assay for the identification of small molecule inhibitors of the Lin28-pre-let-7 interaction. A library of pharmacologically active small molecules was screened and several small molecule inhibitors were identified and biochemically validated. Of these four validated inhibitors, two compounds successfully restored processing of pre-let-7g in the presence of Lin28, validating the concept. Thus, we have identified examples of small molecule inhibitors of the interaction between Lin28 and pre-let-7. This study provides a proof of concept for small molecule inhibitors that antagonise the effects of Lin28 and enhance processing of let-7 miRNA.

  2. LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency.

    Science.gov (United States)

    Tsanov, Kaloyan M; Pearson, Daniel S; Wu, Zhaoting; Han, Areum; Triboulet, Robinson; Seligson, Marc T; Powers, John T; Osborne, Jihan K; Kane, Susan; Gygi, Steven P; Gregory, Richard I; Daley, George Q

    2017-01-01

    Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.

  3. Lin28/let-7/Bcl-xL pathway: the underlying mechanism of drug resistance in Hep3B cells.

    Science.gov (United States)

    Tian, Nan; Han, Ziwu; Li, Zhaohui; Zhou, Mingjie; Fan, Chunlei

    2014-09-01

    Hepatocellular carcinoma (HCC) is highly resistant to chemotherapeutic drugs, which markedly reduces the effect of chemotherapy. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemotherapy drug resistance is unknown. In the present study, we established a drug-resistant Hep3B cell line to investigate the association between Lin28 and drug resistance in HCC, and we identified the underlying mechanisms. We found that the expression of Lin28 was closely associated with resistance to paclitaxel. The drug‑resistant Hep3B cell line, which expresses high levels of Lin28, is more resistant to paclitaxel and other anticancer drugs than the parental cell line. Moreover, further studies showed that dysregulation of Lin28 inhibited let-7 family microRNA levels and upregulated the anti-apoptotic protein Bcl-xL, which is a target of let-7. Our results indicate that the Lin28/let-7/Bcl-xL pathway underlies the drug resistance of Hep3B cells.

  4. Does Lin28 antagonize miRNA-mediated repression by displacing miRISC from target mRNAs?

    Directory of Open Access Journals (Sweden)

    Amanda N Kallen

    2012-11-01

    Full Text Available Lin28 is a developmentally regulated RNA-binding protein that plays important roles in diverse physiological and pathological processes including oncogenesis and brain synaptic function. These pleiotropic roles of Lin28 are mechanistically linked both to its ability to directly stimulate translation of genes involved primarily in cell growth and metabolism and to its ability to block biogenesis of a subset of miRNAs including the let-7 family of miRNAs. In the case of direct stimulation of gene expression, Lin28 binds to targeted mRNAs through recognition of Lin28-responsive elements (LREs within mRNAs and recruits RNA helicase A (RHA to promote translation. RHA belongs to the DEAD-box protein family of RNA helicases, which generally catalyze ATP-dependent unwinding of RNA duplexes or remodeling of ribonucleoprotein complexes (RNPs. Since any given mRNA can potentially be inhibited by miRNAs bearing complementary sequences, we hypothesize that binding of Lin28 to LREs not only nucleates the binding of multiple Lin28 molecules to the same mRNA, but also leads to remodeling of RNPs through recruitment of RHA and causes release of inhibitory miRNA-induced silencing complexes (miRISCs bound to the mRNA. This mode of action may contribute to Lin28-mediated stimulation of translation in both tumor and neuronal cells.

  5. Using NMR to Identify Structural Features of Lin28-Regulated miRNAs and mRNAs and as a Tool for Comparing Differences in Cellular Metabolism

    OpenAIRE

    O'Day, Elizabeth Mary

    2013-01-01

    Part 1 of this thesis seeks to identify shared structural features of Lin28-regulated miRNAs and mRNAs. Lin28 is an evolutionarily conserved, RNA binding protein, highly expressed in stem cells and poorly differentiated cancers, that inhibits differentiation and helps maintain stem cell properties. Lin28 binds to both the loops of let-7 precursors to block let-7 biogenesis and to Lin28 responsive elements (LREs) in mRNAs either to enhance or inhibit translation. Lin28 RNA binding properties a...

  6. LIN28: a regulator of tumor-suppressing activity of let-7 microRNA in human breast cancer.

    Science.gov (United States)

    Sakurai, Minako; Miki, Yasuhiro; Masuda, Mariko; Hata, Shuko; Shibahara, Yukiko; Hirakawa, Hisashi; Suzuki, Takashi; Sasano, Hironobu

    2012-09-01

    A tumor-suppressor gene, let-7 microRNA (miRNA) family, is often inactivated in various human malignancies. LIN28 is a RNA-binding protein that has been well characterized for regulation of let-7 maturation in undifferentiated embryonic stem cells at post-transcriptional level. Oncogenic regulation of let-7 miRNAs has been demonstrated in several human malignancies but their correlation with LIN28 has not been studied in breast cancer. We therefore explored a possible mechanism of tumorigenesis in breast carcinoma tissue via an alternation of let-7 miRNA precursor processing by LIN28 in this study. A total of 26 breast cancer surgical pathology specimens were evaluated for LIN28 and LIN28B expression using immunohistochemistry. We then isolated carcinoma cells in 21 cases using laser capture microdissection, and the miRNAs from these samples were profiled using PCR array analysis. LIN28 status was positively correlated with ERα, PR, and Ki-67 status and inversely correlated with HER2 status. These results suggest the possible involvement of LIN28 in regulation of sex steroid dependent cell proliferation of breast carcinoma cells. We further demonstrated that expression of let-7a, let-7c, let-7d (P=0.026) and let-7f (P=0.016) were inversely correlated with those of LIN28. These results also suggest that LIN28 promotes tumorigenic activity by suppressing let-7 miRNA maturation in breast carcinoma cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Lin28 regulates the expression of neuropeptide Y receptors and oocyte-specific homeobox genes in mouse embryonic stem cells.

    Science.gov (United States)

    Park, Geon Tae; Seo, You-Mi; Lee, Su-Yeon; Lee, Kyung-Ah

    2012-06-01

    Lin28 has been known to control the proliferation and pluripotency of embryonic stem cells. The purpose of this study was to determine the downstream effectors of Lin28 in mouse embryonic stem cells (mESCs) by RNA interference and microarray analysis. The control siRNA and Lin28 siRNA (Dharmacon) were transfected into mESCs. Total RNA was prepared from each type of transfected mESC and subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis to confirm the downregulation of Lin28. The RNAs were labeled and hybridized with an Affymetrix Gene-Chip Mouse Genome 430 2.0 array. The data analysis was accomplished by GenPlex 3.0 software. The expression levels of selected genes were confirmed by quantitative real-time RT-PCR. According to the statistical analysis of the cDNA microarray, a total of 500 genes were altered in Lin28-downregulated mESCs (up-regulated, 384; down-regulated, 116). After differentially expressed gene filtering, 31 genes were selected as candidate genes regulated by Lin28 downregulation. Among them, neuropeptide Y5 receptor and oocyte-specific homeobox 5 genes were significantly upregulated in Lin28-downregulated mESCs. We also showed that the families of neuropeptide Y receptor (Npyr) and oocyte-specific homeobox (Obox) genes were upregulated by downregulation of Lin28. Based on the results of this study, we suggest that Lin28 controls the characteristics of mESCs through the regulation of effectors such as the Npyr and Obox families.

  8. Intron-specific patterns of divergence of lin-11 regulatory function in the C. elegans nervous system.

    Science.gov (United States)

    Amon, Siavash; Gupta, Bhagwati P

    2017-04-01

    The diversity of neurons in the nervous system is specified by many genes, including those that encode transcription factors (TFs) and play crucial roles in coordinating gene transcription. To understand how the spatiotemporal expression of TF genes is regulated to generate neuronal diversity, we used one member of the LIM-Hox family, lin-11, as a model that is necessary for the differentiation of amphid neurons in the nematode C. elegans and a related species C. briggsae. We characterized transcriptional regulation of lin-11 and uncovered regulatory roles of two of the largest introns, intron 3 and intron 7. These introns promote lin-11 expression in non-overlapping sets of neurons. Phenotypic rescue experiments in C. elegans revealed that intron 3 is capable of restoring lin-11 function based on gene expression patterns and behavioral assays. Interestingly, intron 3-driven reporter expression showed differences in neuronal cell types between C. briggsae and C. elegans, indicating evolutionary changes in lin-11 regulation between the two species. Reciprocal transformation experiments provided further evidence consistent with functional changes in both cis and trans regulation of lin-11. To further investigate transcriptional regulation of lin-11, we dissected the intronic regions in C. elegans and identified cell-specific enhancers. These enhancers possess multiple sequence blocks that are conserved among Caenorhabditis species and possess TF binding sites. We tested the role of a subset of predicted TFs and discovered that while three of them (SKN-1, CEH-6, and CRH-1) act via the intron 3 enhancer to negatively regulate lin-11 expression in neurons, another TF (CES-1) acts positively via the intron 7 enhancer. Overall, our findings demonstrate that neuronal expression of lin-11 involves multiple TF regulators and regulatory modules some of which have diverged in Caenorhabditis nematodes.

  9. Testicular expression of the Lin28/let-7 system: Hormonal regulation and changes during postnatal maturation and after manipulations of puberty.

    Science.gov (United States)

    Sangiao-Alvarellos, S; Manfredi-Lozano, M; Ruiz-Pino, F; León, S; Morales, C; Cordido, F; Gaytán, F; Pinilla, L; Tena-Sempere, M

    2015-10-23

    The Lin28/let-7 system, which includes the RNA-binding proteins, Lin28a/Lin28b, and let-7 miRNAs, has emerged as putative regulator of puberty and male gametogenesis; yet, its expression pattern and regulation in postnatal testis remain ill defined. We report herein expression profiles of Lin28 and let-7 members, and related mir-145 and mir-132, in rat testis during postnatal maturation and in models of altered puberty and hormonal deregulation. Neonatal expression of Lin28a and Lin28b was low and rose markedly during the infantile period; yet, expression patterns diverged thereafter, with persistently elevated levels only for Lin28b, which peaked at puberty. Let-7a, let-7b, mir-132 and mir-145 showed profiles opposite to Lin28b. In fact, let-7b and mir-145 were abundant in pachytene spermatocytes, but absent in elongating spermatids, where high expression of Lin28b was previously reported. Perturbation of puberty by neonatal estrogenization reverted the Lin28/let-7 expression ratio; expression changes were also detected in other models of delayed puberty, due to early photoperiod or nutritional manipulations. In addition, hypophysectomy or growth hormone (GH) deficiency revealed regulation of this system by gonadotropins and GH. Our data document the expression profiles of the Lin28/let-7 system in rat testis along postnatal/pubertal maturation, and their perturbation in models of pubertal and hormonal manipulation.

  10. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Lin28A activates androgen receptor via regulation of c-myc and promotes malignancy of ER-/Her2+ breast cancer.

    Science.gov (United States)

    Shen, Honghong; Zhao, Lin; Feng, Xiaolong; Xu, Cong; Li, Congying; Niu, Yun

    2016-09-13

    Having previously demonstrated the co-expression status of the Lin28A and androgen receptor (AR) in ER-/Her2+ breast cancer, we tested the hypothesis that Lin28A can activate AR and promotes growth of ER-/Her2+ breast cancer. The expression of Lin28A and AR were examined after Lin28A siRNA and Lin28A plasmid were transfected into ER-/Her2+ breast cancer cells. Chromatin immune-precipitation (ChIP) analysis and Luciferase Assays were used to evaluate the effect of Lin28A and c-myc on AR promoter activity. MTT assays, Boyden chamber invasion assays, colony formation assays and flow cytometry analysis were performed. ER-/Her2+ breast cancer cells which transfected with Lin28A siRNAs and Lin28A plasmid were injected into nude mice, and tumorigenesis was monitored. Our data showed that Lin28A can induced AR expression in ER-/Her2+ breast cancer cells. ChIP analysis showed that Lin28A stimulates the recruitment of c-Myc to the promoter of the AR gene. Lin28A enhanced growth ability, colonies ability, cells proliferation activities, invasive ability and inhibited cells apoptosis of ER-/Her2+ breast cancer cells. Lin28A high expression cells exhibited significantly higher tumorigenic ability in vivo. Our study demonstrates that Lin28A can activates androgen receptor via regulation of c-myc and promotes malignancy of ER-/Her2+ breast cancer. Our findings underline a novel role for Lin28A in breast cancer development and activation of the AR axis.

  12. Lin28A activates androgen receptor via regulation of c-myc and promotes malignancy of ER−/Her2+ breast cancer

    Science.gov (United States)

    Shen, Honghong; Zhao, Lin; Feng, Xiaolong; Xu, Cong; Li, Congying; Niu, Yun

    2016-01-01

    Having previously demonstrated the co-expression status of the Lin28A and androgen receptor (AR) in ER−/Her2+ breast cancer, we tested the hypothesis that Lin28A can activate AR and promotes growth of ER−/Her2+ breast cancer. The expression of Lin28A and AR were examined after Lin28A siRNA and Lin28A plasmid were transfected into ER−/Her2+ breast cancer cells. Chromatin immune-precipitation (ChIP) analysis and Luciferase Assays were used to evaluate the effect of Lin28A and c-myc on AR promoter activity. MTT assays, Boyden chamber invasion assays, colony formation assays and flow cytometry analysis were performed. ER−/Her2+ breast cancer cells which transfected with Lin28A siRNAs and Lin28A plasmid were injected into nude mice, and tumorigenesis was monitored. Our data showed that Lin28A can induced AR expression in ER−/Her2+ breast cancer cells. ChIP analysis showed that Lin28A stimulates the recruitment of c-Myc to the promoter of the AR gene. Lin28A enhanced growth ability, colonies ability, cells proliferation activities, invasive ability and inhibited cells apoptosis of ER−/Her2+ breast cancer cells. Lin28A high expression cells exhibited significantly higher tumorigenic ability in vivo. Our study demonstrates that Lin28A can activates androgen receptor via regulation of c-myc and promotes malignancy of ER−/Her2+ breast cancer. Our findings underline a novel role for Lin28A in breast cancer development and activation of the AR axis. PMID:27494865

  13. Lin28 mediates radiation resistance of breast cancer cells via regulation of caspase, H2A.X and Let-7 signaling.

    Science.gov (United States)

    Wang, Linbo; Yuan, Chao; Lv, Kezhen; Xie, Shuduo; Fu, Peifen; Liu, Xiaojiao; Chen, Yongxia; Qin, Chuan; Deng, Wuguo; Hu, Wenxian

    2013-01-01

    Resistance to radiation therapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to breast tumorigenesis; however, the relationship between Lin28 and radioresistance remains unknown. In this study, we investigated the association of Lin28 with radiation resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines. The results showed that the expression level of Lin28 was closely associated with resistance to radiation treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to radiation than MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which have low-level Lin28 expression. Transfection with Lin28 siRNA significantly led to an increase of sensitivity to radiation. By contrast, stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to radiation treatment. Stable expression of Lin28 also significantly inhibited radiation-induced apoptosis. Moreover, further studies have shown that caspases, H2A.X and Let-7 miRNA were the molecular targets of Lin28. Stable expression of Lin28 and treatment with radiation induced H2AX expression, while inhibited p21 and γ-H2A.X. Overexpression of Let-7 enhanced the sensitivities to radiation in breast cancer cells. Taken together, these results indicate that Lin28 might be one mechanism underlying radiation resistance, and Lin28 could be a potential target for overcoming radiation resistance in breast cancer.

  14. Lin28 mediates radiation resistance of breast cancer cells via regulation of caspase, H2A.X and Let-7 signaling.

    Directory of Open Access Journals (Sweden)

    Linbo Wang

    Full Text Available Resistance to radiation therapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to breast tumorigenesis; however, the relationship between Lin28 and radioresistance remains unknown. In this study, we investigated the association of Lin28 with radiation resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines. The results showed that the expression level of Lin28 was closely associated with resistance to radiation treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to radiation than MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which have low-level Lin28 expression. Transfection with Lin28 siRNA significantly led to an increase of sensitivity to radiation. By contrast, stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to radiation treatment. Stable expression of Lin28 also significantly inhibited radiation-induced apoptosis. Moreover, further studies have shown that caspases, H2A.X and Let-7 miRNA were the molecular targets of Lin28. Stable expression of Lin28 and treatment with radiation induced H2AX expression, while inhibited p21 and γ-H2A.X. Overexpression of Let-7 enhanced the sensitivities to radiation in breast cancer cells. Taken together, these results indicate that Lin28 might be one mechanism underlying radiation resistance, and Lin28 could be a potential target for overcoming radiation resistance in breast cancer.

  15. Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation

    National Research Council Canada - National Science Library

    Choudhury, Nila Roy; Nowak, Jakub S; Zuo, Juan; Rappsilber, Juri; Spoel, Steven H; Michlewski, Gracjan

    2014-01-01

    .... Lin28a is a conserved RNA binding protein involved in pluripotency and tumorigenesis that was previously shown to trigger TuT4-mediated pre-let-7 uridylation, inhibiting its processing and targeting it for degradation...

  16. Response to Niklasson's comment on Lin, et al. (2012) : "the relation between postural movement and bilateral motor integration".

    Science.gov (United States)

    Lin, Chin-Kai; Kuo, Bor-Chen; Wu, Huey-Min

    2014-10-01

    In the study of Lin, Wu, Lin, Wu, Wu, Kuo, and Yeung (2012 ), the relationship between the validity of postural movement and bilateral motor integration in terms of sensory integration theory was examined. Postural movement is the ability to use the antigravity postures required for stabilization of the neck, trunk and upper extremities via muscle co-contractions in the neck and upper extremities, and balance. Niklasson's (2013 ) comment argued that postural movement should include primitive reflexes in terms of the general abilities approach. Niklasson (2013 ) focused on the efficacy of the treatment rather than the theoretical frameworks implied in the therapeutic activities. For that purpose Lin, et al. (2012 ) used sensory integration as the theoretical foundation, and the relationship between postural movement and bilateral motor integration was assessed via empirical data. The result of Lin, et al. (2012 ) was offered as a theoretical reference for therapeutic activities.

  17. Fragmented Encounters, Social Slippages: Lin Huiyin's "In Ninety-Nine Degree Heat"

    Directory of Open Access Journals (Sweden)

    Carles Prado-Fonts

    2010-01-01

    Full Text Available The article reads Lin Huiyin’s short story “In Ninety-Nine Degree Heat” (1934 in relation to the context of 1930s China, as an innovative literary work which combines elements from both the Chinese and the Western traditions, and as a text which informs readers not only of the problematic of class and gender issues in 1930s Chinese society but also of the context of the liuxuesheng who returns to China –like Lin Huiyin herself. Focusing on questions like otherness, representation, and encounters, the essay analyzes how the episodic narrative structure of Lin’s short story echoes social and representational discourses in post-May Fourth China, at the same time that it explores issues such as social inequality, otherness and alienation, which were crucial to the liuxuesheng, and which reflect Lin’s own experience as a returned and alienated liuxuesheng at the time.

  18. A Comparative Study on Different Fates between Jane Eyre and Lin Daiyu

    Institute of Scientific and Technical Information of China (English)

    林冬梅; 赵慧

    2014-01-01

    Jane Eyre and A Dream of Red Mansions can be regarded as the most famous two classics in the history of literature. In A Dream of Red Mansions, Cao Xueqin exhausted almost all his heart and soul to portray the character─Lin Daiyu, whose tragic and impressive love story has moved thousands of readers into tears. While, Charlotte Bronte ’s Jane Eyre raised heated discussion in 19th century because of the vivid and energetic female she depicted in her book. By comparison, it is easy to find that there are some similarities between the two characters. However, their fates are quite different. This paper tries to make a comparison be-tween Jane Eyre and Lin Daiyu, review their life experience, analyze possible reasons that may account for the different fates, and draw a conclusion. Hope that this paper can do some help to those who are interested in literature home and abroad.

  19. Caractéristiques des huiles de lin et de chanvre

    Directory of Open Access Journals (Sweden)

    Morin Odile

    2015-11-01

    Full Text Available Les huiles de lin et de chanvre appartiennent à la famille des huiles riches en acides gras polyinsaturés contenant de l’acide alpha-linolénique (ALA. Le contexte actuel du déficit d’apport en ALA, précurseur indispensable des AGPI de la série des omégas 3 (ou n-3, comme en ses dérivés métaboliques supérieurs (EPA, DHA, fonde le regain d’intérêt pour les sources apportant le précurseur de ces acides gras essentiels. Les autorisations de commercialisation de l’huile de chanvre ou l’évolution réglementaire dans le cas de l’huile de lin en France, ont tenu compte de cet atout nutritionnel pourvu que les conditions de stabilité en conservation soient garanties.

  20. An Algorithmic Complexity Interpretation of Lin's Third Law of Information Theory

    Directory of Open Access Journals (Sweden)

    Joel Ratsaby

    2008-03-01

    Full Text Available Instead of static entropy we assert that the Kolmogorov complexity of a static structure such as a solid is the proper measure of disorder (or chaoticity. A static structure in a surrounding perfectly-random universe acts as an interfering entity which introduces local disruption in randomness. This is modeled by a selection rule R which selects a subsequence of the random input sequence that hits the structure. Through the inequality that relates stochasticity and chaoticity of random binary sequences we maintain that Lin’s notion of stability corresponds to the stability of the frequency of 1s in the selected subsequence. This explains why more complex static structures are less stable. Lin’s third law is represented as the inevitable change that static structure undergo towards conforming to the universe’s perfect randomness.

  1. Structural and electronic properties of stable Lin (n=2-10) clusters: A density functional study

    Science.gov (United States)

    Chetri, Pawan; Deka, Ramesh Ch.; Choudhury, Amarjyoti

    2013-12-01

    Structure and relative stability of Lin clusters for n=1-10 were investigated using density functional methods based DMol3 program. The structures of Li clusters were determined in terms of Li-Li bond length and the results are in very good agreement with experimental values. Stability of the clusters was determined from their relative energy values binding energies and second difference energy. We also determined fragmentation energy of each size of cluster. We arrived at some interesting result like the transition of Lin from 2-dimension to 3-dimension for a particular value of n and also the variation of HOMO-LUMO gap with cluster size. Many structures are characterized for the first time in this work.

  2. Manipulation quantique de la lumière par un amplificateur non linéaire

    Science.gov (United States)

    Symul, T.; Bencheikh, K.; Levenson, J. A.

    2002-06-01

    Nous proposons un dispositif original, appelé Amplificateur Non Linéaire (ANL), permettant la génération et la manipulation d'états quantiques de la lumière. Ce dispositif permet une compression du bruit quantique de la lumière en dessous de la limite quantique standard plus efficace que celle obtenue par interactions non linéaires du second ordre ou du troisième ordre. Il permet également d'inverser les fluctuations quantiques en intensité de la lumière, et de produire des photons jumeaux ayant des corrélations quantiques plus élevées et plus robustes que ceux produits par un amplificateur paramétrique seul.

  3. GENII-LIN: a Multipurpose Health Physics Code Built on GENII-1.485

    Directory of Open Access Journals (Sweden)

    Marco Sumini

    2006-10-01

    Full Text Available The aim of the GENII-LIN project was to develop an open source multipurpose health physics code running on Linux platform, for calculating radiation dose and risk from radionuclides released to the environment. The general features of the GENII-LIN system include [1] capabilities for calculating radiation dose both for acute and chronic releases, with options for annual dose, committed dose and accumulated dose [2] capabilities for evaluating exposure pathways including direct exposure via water (swimming, boating, fishing, soil (buried and surface sources and air (semi-infinite cloud and finite cloud model, inhalation pathways and ingestion pathways. The release scenarios considered are: - acute release to air, from ground level or elevated sources, or to water; - chronic release to air, from ground level or elevated sources, or to water; - initial contamination of soil or surfaces. Keywords: radiation protection, Linux, health physics, risk analysis.

  4. Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Ao-Xiang Chen

    2011-09-01

    Full Text Available Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300 demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR of 1.25 (P = 0.0091, which was successfully replicated in a second independent study (n = 1,156 with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻⁵. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

  5. Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.

    Science.gov (United States)

    Chen, Ao-Xiang; Yu, Ke-Da; Fan, Lei; Li, Ji-Yu; Yang, Chen; Huang, A-Ji; Shao, Zhi-Ming

    2011-09-01

    Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻⁵. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

  6. The expression of the let-7 miRNAs and Lin28 signalling pathway in human term gestational tissues.

    Science.gov (United States)

    Chan, H W; Lappas, M; Yee, S W Yi; Vaswani, K; Mitchell, M D; Rice, G E

    2013-05-01

    Labour and delivery are processes associated with inflammation within intrauterine and cervical tissues. The mechanisms that induce labour-associated changes and, in particular, the role of microRNAs (miRNAs) remain to be elucidated. MiRNAs are small non-coding RNAs that repress gene expression via mRNA degradation and translational repression. Let-7 miRNAs are negatively regulated by RNA-binding protein, Lin28, and both function downstream of NF-κB signalling. In non-gestational tissues, let-7 and Lin28 reportedy function as negative and positive regulators of IL-6 expression. We hypothesised that labour-associated inflammation involves the downregulation of let-7 miRNAs and upregulation of Lin28 expression. To determine the expression of Lin28 protein and let-7 miRNA in human gestational tissue obtained before and after labour. Gestational tissues were collected from women at term by Caesarean section with and without labour and following normal vaginal delivery (n = 6 per group). Protein and RNA was extracted and Lin28 and let-7 miRNA expression was measured by Western blotting and real-time PCR. The data obtained established that let-7 miRNA and Lin28 display tissue-specific expression: Lin28 was strongly expressed in the placenta and choriodecidua, but not measurable in amnion; and let-7b and -7c expression were significantly lower in choriodecidua compare to placenta and amnion, whereas the amnion expressed less let-7d and -7f than other tissues. While the expression of Lin28 protein and let-7 miRNA did not vary significantly with labour onset and delivery, changes in their bioactivity and impact on nuclear signalling pathways in human gestational tissues remain to be established. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A.

    Science.gov (United States)

    Chaudhuri, Aadel A; So, Alex Yick-Lun; Mehta, Arnav; Minisandram, Aarathi; Sinha, Nikita; Jonsson, Vanessa D; Rao, Dinesh S; O'Connell, Ryan M; Baltimore, David

    2012-03-13

    MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.

  8. LIN28A marks the spermatogonial progenitor population and regulates its cyclic expansion.

    Science.gov (United States)

    Chakraborty, Papia; Buaas, F William; Sharma, Manju; Snyder, Elizabeth; de Rooij, Dirk G; Braun, Robert E

    2014-04-01

    One of the hallmarks of highly proliferative adult tissues is the presence of a stem cell population that produces progenitor cells bound for differentiation. Progenitor cells undergo multiple transit amplifying (TA) divisions before initiating terminal differentiation. In the adult male germline, daughter cells arising from the spermatogonial stem cells undergo multiple rounds of TA divisions to produce undifferentiated clones of interconnected 2, 4, 8, and 16 cells, collectively termed A(undifferentiated) (A(undiff)) spermatogonia, before entering a stereotypic differentiation cascade. Although the number of TA divisions markedly affects the tissue output both at steady state and during regeneration, mechanisms regulating the expansion of the TA cell population are poorly understood in mammals. Here, we show that mice with a conditional deletion of Lin28a in the adult male germline, display impaired clonal expansion of the progenitor TA A(undiff) spermatogonia. The in vivo proliferative activity of Au(ndiff) spermatogonial cells as indicated by BrdU incorporation during S-phase was reduced in the absence of LIN28A. Thus, contrary to the role of LIN28A as a key determinant of cell fate signals in multiple stem cell lineages, in the adult male germline it functions as an intrinsic regulator of proliferation in the population of A(undiff) TA spermatogonia. In addition, neither precocious differentiation nor diminished capacity for self-renewal potential as assessed by transplantation was observed, suggesting that neither LIN28A itself nor the pool of Aal progenitor cells substantially contribute to the functional stem cell compartment. © AlphaMed Press.

  9. Professor LIAN Yu-lin's Experience in Treating Gynecological Disorders by Acupuncture

    Institute of Scientific and Technical Information of China (English)

    尚方明

    2006-01-01

    @@ Professor LIAN Yu-lin, a chief doctor in the acupuncture department of the first affiliated hospital of Tianjin College of Traditional Chinese Medicine, has been engaged himself in Chinese medicine for over 30 years with perfect medical skills and rich experience in the treatment of cerebrovascular diseases and cervical and lumbar diseases, especially in the treatment of gynecological disorders by acupuncture. I follow professor Lian as an intern and have learnt some skillful techniques in the treatment of gynecological disorders by acupuncture.

  10. Search for the Halo Effect in the 1H(6He, 6Li)n Peaction

    Institute of Scientific and Technical Information of China (English)

    李志宏; 柳卫平; 白希祥; 王友宝; 连钢; 李志常; 申庆彪; 林承键; 曾晟; 符长波

    2002-01-01

    The angular distributions of the charge exchange reaction 1 H(6He, 6Li)n were measured in reverse kinematics with a secondary 6He beam at the energy of4.17 AMeV. The data were analysed in the context ora microscopic calculation. It is shown that both the ground state of6He and the second excited state of6Li (3.563 MeV, 0+) have a halo structure.

  11. [Exploration of the application of detective pressing method in LIN's scalp acupuncture].

    Science.gov (United States)

    Wang, Hai-Li

    2011-05-01

    The origin, theoretic basis and operation of detective pressing method in clinical application of LIN's scalp acupuncture are introduced in this paper and its advantages in clinical practice are explored. It is found that the therapy could reduce the sense of fear in patients, localize the points precisely, guide treatment and develop the ideas of treatment. Under the guide of modern science in the brain, the therapy could be used to treat much more cerebral diseases.

  12. Studies on the Translation Theory and Translation Practice of Lin Yutang through Moment in Peking

    Institute of Scientific and Technical Information of China (English)

    姚驰

    2014-01-01

    This paper makes studies on the translation theory and translation practice of Lin Yutang through Moment in Peking. First the paper describes Lin’s achievements and translation theories mainly from his work on translation and then associates them with his world-renowned novel Moment in Peking to testify those effective theories, indicating that translators should take on the responsibility of introducing Chinese culture and promoting the communication between countries.

  13. Studies on the Translation Theory and Translation Practice of Lin Yutang through Moment in Peking

    Institute of Scientific and Technical Information of China (English)

    姚驰

    2014-01-01

    This paper makes studies on the translation theory and translation practice of Lin Yutang through Moment in Peking.First the paper describes Lin’s achievements and translation theories mainly from his work on translation and then associates them with his world-renowned novel Moment in Peking to testify those effective theories, indicating that translators should take on the responsibility of introducing Chinese culture and promoting the communication between countries.

  14. Lin28b Regulates Fetal Regulatory T Cell Differentiation through Modulation of TGF-β Signaling.

    Science.gov (United States)

    Bronevetsky, Yelena; Burt, Trevor D; McCune, Joseph M

    2016-12-01

    Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to noninherited Ags on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4(+)FOXP3(+)CD25(+) regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared with adult T cells, fetal naive CD4(+) T cells exhibit a strong predisposition to differentiate into Tregs when stimulated. This effect is mediated by the TCR and TGF-β pathways, and fetal T cells show significantly increased Treg differentiation in response to anti-CD3 and TGF-β stimulation. Naive fetal T cells also exhibit increased signaling through the TGF-β pathway, with these cells demonstrating increased expression of the signaling mediators TGF-βRI, TGF-βRIII, and SMAD2, and higher levels of SMAD2/SMAD3 phosphorylation. Increased fetal Treg differentiation is mediated by the RNA-binding protein Lin28b, which is overexpressed in fetal T cells as compared with adult cells. When Lin28b expression is decreased in naive fetal T cells, they exhibit decreased Treg differentiation that is associated with decreased TGF-β signaling and lowered expression of TGF-βRI, TGF-βRIII, and SMAD2. Lin28b regulates the maturation of let-7 microRNAs, and these TGF-β signaling mediators are let-7 targets. We hypothesize that loss of Lin28b expression in fetal T cells leads to increased mature let-7, which causes decreased expression of TGF-βRI, TGF-βRIII, and SMAD2 proteins. A reduction in TGF-β signaling leads to reduced Treg numbers. Copyright © 2016 by The American Association of Immunologists, Inc.

  15. 78 Rôle hydrogéologique des linéaments structuraux en milieu ...

    African Journals Online (AJOL)

    TEDDY

    dans l'exploration pétrolière et minérale, le stockage des déchets radioactifs et .... Figure 3 : Linéaments majeurs et répartition spatiale des forages échantillonnés ..... l'espace d'étude et leur degré d'exploitabilité est meilleur par rapport aux ...

  16. Primordial Dwarfism Gene Maintains Lin28 Expression to Safeguard Embryonic Stem Cells from Premature Differentiation

    Directory of Open Access Journals (Sweden)

    Qian Dai

    2014-05-01

    Full Text Available Primordial dwarfism (PD is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7 have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb. Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size.

  17. Dynamiques complexes et morphogenèse Introduction aux sciences non linéaires

    CERN Document Server

    Misbah, Chaouqi

    2011-01-01

    Les sciences non linéaires ont pour objet l’ensemble des phénomènes dont l’analyse résiste au principe de superposition. Elles concernent en grande partie les systèmes dits « complexes » dont l’interaction et l’interdépendance entre les parties empêchent de prédire précisément l’évolution du système. Pour expliquer ces phénomènes, deux approches complémentaires ont été proposées : la théorie des bifurcations et la théorie des catastrophes. Mais la pleine compréhension et la modélisation de la non-linéarité restent chacune un défi pour les scientifiques du XXIe siècle. C’est dans la perspective d’accompagner tous ceux qui voudront le relever que ce livre a été conçu. Son objectif est d’exposer au lecteur le langage et le formalisme nécessaires à l’étude de la non-linéarité. Partant d’exemples simples, pour ensuite atteindre un niveau d’abstraction visant l’universalité, l’auteur explore les divers scénarios possibles de bifurcations et les catastr...

  18. Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation.

    Science.gov (United States)

    Dai, Qian; Luan, Guangxin; Deng, Li; Lei, Tingjun; Kang, Han; Song, Xu; Zhang, Yujun; Xiao, Zhi-Xiong; Li, Qintong

    2014-05-08

    Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia

    Science.gov (United States)

    Chen, Lili; Sun, Yuqing; Wang, Jingya; Jiang, Hui; Muntean, Andrew G.

    2016-01-01

    MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features. c-Myc protein levels were highly correlative with AML disease latency in mice. Functionally, overexpression of c-Myc resulted in a more aggressive proliferation rate in MLL-FP cell lines. While all MLL-FP transformed cells displayed sensitivity to BET inhibitors, high c-Myc expressing cells showed greater resistance to Brd4 inhibition. The Myc target Lin28B was also differentially expressed in MLL-FP cell lines in agreement with c-Myc expression. Examination of Lin28B miRNAs targets revealed that let-7g was significantly increased in leukemic cells associated with the longest disease latency and forced let-7g expression induced differentiation of leukemic blasts. Thus, differential regulation of the c-Myc/Lin28/let-7g program by different MLL-FPs is functionally related to disease latency and BET inhibitor resistance in MLL leukemias. PMID:27007052

  20. High LIN28A Expressing Ovarian Cancer Cells Secrete Exosomes That Induce Invasion and Migration in HEK293 Cells

    Directory of Open Access Journals (Sweden)

    Vanessa A. Enriquez

    2015-01-01

    Full Text Available Epithelial ovarian cancer is the most aggressive and deadly form of ovarian cancer and is the most lethal gynecological malignancy worldwide; therefore, efforts to elucidate the molecular factors that lead to epithelial ovarian cancer are essential to better understand this disease. Recent studies reveal that tumor cells release cell-secreted vesicles called exosomes and these exosomes can transfer RNAs and miRNAs to distant sites, leading to cell transformation and tumor development. The RNA-binding protein LIN28 is a known marker of stem cells and when expressed in cancer, it is associated with poor tumor outcome. We hypothesized that high LIN28 expressing ovarian cancer cells secrete exosomes that can be taken up by nontumor cells and cause changes in gene expression and cell behavior associated with tumor development. IGROV1 cells were found to contain high LIN28A and secrete exosomes that were taken up by HEK293 cells. Moreover, exposure to these IGROV1 secreted exosomes led to significant increases in genes involved in Epithelial-to-Mesenchymal Transition (EMT, induced HEK293 cell invasion and migration. These changes were not observed with exosomes secreted by OV420 cells, which contain no detectable amounts of LIN28A or LIN28B. No evidence was found of LIN28A transfer from IGROV1 exosomes to HEK293 cells.

  1. High LIN28A Expressing Ovarian Cancer Cells Secrete Exosomes That Induce Invasion and Migration in HEK293 Cells.

    Science.gov (United States)

    Enriquez, Vanessa A; Cleys, Ellane R; Da Silveira, Juliano C; Spillman, Monique A; Winger, Quinton A; Bouma, Gerrit J

    2015-01-01

    Epithelial ovarian cancer is the most aggressive and deadly form of ovarian cancer and is the most lethal gynecological malignancy worldwide; therefore, efforts to elucidate the molecular factors that lead to epithelial ovarian cancer are essential to better understand this disease. Recent studies reveal that tumor cells release cell-secreted vesicles called exosomes and these exosomes can transfer RNAs and miRNAs to distant sites, leading to cell transformation and tumor development. The RNA-binding protein LIN28 is a known marker of stem cells and when expressed in cancer, it is associated with poor tumor outcome. We hypothesized that high LIN28 expressing ovarian cancer cells secrete exosomes that can be taken up by nontumor cells and cause changes in gene expression and cell behavior associated with tumor development. IGROV1 cells were found to contain high LIN28A and secrete exosomes that were taken up by HEK293 cells. Moreover, exposure to these IGROV1 secreted exosomes led to significant increases in genes involved in Epithelial-to-Mesenchymal Transition (EMT), induced HEK293 cell invasion and migration. These changes were not observed with exosomes secreted by OV420 cells, which contain no detectable amounts of LIN28A or LIN28B. No evidence was found of LIN28A transfer from IGROV1 exosomes to HEK293 cells.

  2. Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.

    Science.gov (United States)

    Gunsalus, Kearney T W; Wagoner, Matthew P; Meyer, Kassondra; Potter, Wyatt B; Schoenike, Barry; Kim, Soyoung; Alexander, Caroline M; Friedl, Andreas; Roopra, Avtar

    2012-07-01

    The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo. ©2012 AACR.

  3. Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective

    Science.gov (United States)

    Mayr, Florian; Heinemann, Udo

    2013-01-01

    Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions. PMID:23939427

  4. Identification of mRNAs bound and regulated by human LIN28 proteins and molecular requirements for RNA recognition

    Science.gov (United States)

    Hafner, Markus; Max, Klaas E.A.; Bandaru, Pradeep; Morozov, Pavel; Gerstberger, Stefanie; Brown, Miguel; Molina, Henrik; Tuschl, Thomas

    2013-01-01

    Human LIN28A and LIN28B are RNA-binding proteins (RBPs) conserved in animals with important roles during development and stem cell reprogramming. We used Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) in HEK293 cells and identified a largely overlapping set of ∼3000 mRNAs at ∼9500 sites located in the 3′ UTR and CDS. In vitro and in vivo, LIN28 preferentially bound single-stranded RNA containing a uridine-rich element and one or more flanking guanosines and appeared to be able to disrupt base-pairing to access these elements when embedded in predicted secondary structure. In HEK293 cells, LIN28 protein binding mildly stabilized target mRNAs and increased protein abundance. The top targets were its own mRNAs and those of other RBPs and cell cycle regulators. Alteration of LIN28 protein levels also negatively regulated the abundance of some but not all let-7 miRNA family members, indicating sequence-specific binding of let-7 precursors to LIN28 proteins and competition with cytoplasmic miRNA biogenesis factors. PMID:23481595

  5. A mirror of two faces: Lin28 as a master regulator of both miRNA and mRNA.

    Science.gov (United States)

    Huang, Yingqun

    2012-01-01

    Lin28 is an evolutionarily conserved RNA-binding protein that plays important roles in development, pluripotency, tumorigenesis, and metabolism. Emerging evidence suggests that the pleiotropic roles of Lin28 in the diverse physiological and pathological processes are mechanistically linked to its ability to modulate not only the biogenesis of miRNAs, particularly the let-7 family miRNAs, but also the translation of mRNAs important for cell growth and metabolism. Let-7 negatively regulates the translation of oncogenes, cell cycle regulators, and metabolic pathway components. Lin28 relieves this repression by blocking the production of mature let-7. Lin28 binds to the terminal loops of let-7 precursors, leading to inhibition of processing and the induction of uridylation and precursor degradation. Lin28 also is a direct translational regulator: it selectively binds to a cohort of mRNAs and stimulates their translation. Recent advances in our understanding of Lin28-mediated mechanisms of posttranscriptional regulation of gene expression reveal important roles of this protein in the fields of development, stem cells, metabolic diseases, and cancer. Copyright © 2012 John Wiley & Sons, Ltd.

  6. Mechanisms of Lin28-mediated miRNA and mRNA regulation--a structural and functional perspective.

    Science.gov (United States)

    Mayr, Florian; Heinemann, Udo

    2013-08-09

    Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28's RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.

  7. Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective

    Directory of Open Access Journals (Sweden)

    Udo Heinemann

    2013-08-01

    Full Text Available Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs, an N-terminal cold-shock domain (CSD and a C-terminal Zn-knuckle domain (ZKD. Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.

  8. Novel localisation and possible function of LIN7 and IRSp53 in mitochondria of HeLa cells.

    Science.gov (United States)

    Ferrari, Ilaria; Crespi, Arianna; Fornasari, Diego; Pietrini, Grazia

    2016-08-01

    By means of immunofluorescence and subcellular fractionation experiments, we here demonstrate mitochondrial distribution of LIN7 and IRSp53 in HeLa cells. These peripheral proteins displayed a tight association with mitochondria and coimmunoprecipitated from mitochondrial fractions. In line with a role for LIN7 in the regulation of IRSp53 activity on actin dynamics, the morphology of mitochondria was similarly altered by changing the expression levels of either each protein or both, whereas mitochondrial morphology was preserved in cells overexpressing IRSp53 deleted of its binding domains for LIN7 (IRSp53Δ5) or for actin polymerisation modulators (IRSp53ΔSH3). In particular, the overexpression of full length LIN7 and/or IRSp53 increased the percentage of cells with short mitochondria, while downregulation of the endogenous proteins by shRNAs increased the amount of cells with elongated and perinuclear clustered mitochondria. These mitochondria were only partially resistant to fragmentation induced by dissipation of the mitochondrial membrane potential (i.e. treatment with sodium azide), whereas mitochondria were fully protected by the fission defective mutant Drp1 K38A. Overexpression of LIN7 or IRSp53 did not prevent the formation of hyperfused mitochondria in cells coexpressing the Drp1 K38A mutant, thus suggesting that LIN7-IRSp53 complex requires functional Drp1 to regulate mitochondrial morphology. Copyright © 2016 Elsevier GmbH. All rights reserved.

  9. Makorin ortholog LEP-2 regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans.

    Science.gov (United States)

    Herrera, R Antonio; Kiontke, Karin; Fitch, David H A

    2016-03-01

    The heterochronic genes lin-28, let-7 and lin-41 regulate fundamental developmental transitions in animals, such as stemness versus differentiation and juvenile versus adult states. We identify a new heterochronic gene, lep-2, in Caenorhabditis elegans. Mutations in lep-2 cause a delay in the juvenile-to-adult transition, with adult males retaining pointed, juvenile tail tips, and displaying defective sexual behaviors. In both sexes, lep-2 mutants fail to cease molting or produce an adult cuticle. We find that LEP-2 post-translationally regulates LIN-28 by promoting LIN-28 protein degradation. lep-2 encodes the sole C. elegans ortholog of the Makorin (Mkrn) family of proteins. Like lin-28 and other heterochronic pathway members, vertebrate Mkrns are involved in developmental switches, including the timing of pubertal onset in humans. Based on shared roles, conservation and the interaction between lep-2 and lin-28 shown here, we propose that Mkrns, together with other heterochronic genes, constitute an evolutionarily ancient conserved module regulating switches in development.

  10. Translating Chinese Place Names into English: The Case of Lin Yutang’s Version of Fusheng Liuji

    Directory of Open Access Journals (Sweden)

    Shuangchang Cui

    2016-04-01

    Full Text Available Chapter Four of Fusheng Liuji (Six Chapters of a Floating Life, a unique autobiographical prose work by early Qing-dynasty author Shen Fu (1763-1825, records Shen's travel to many parts of the country and contains a multitude of place names, whose rich cultural connotations pose a great challenge to the translator. Drawing on Javier Franco Aixelá’s taxonomy of translation strategies for treating culture-specific items, this paper attempts to describe the translation strategies adopted by world-renowned writer and translator Lin Yutang to handle these place names. An analysis of twenty-four examples indicates that Lin tended to preserve Chinese culture carried by the place names through employing cultural conservation strategies, including linguistic translation, transliteration, transliteration plus linguistic translation, transliteration plus annotation, and linguistic translation plus annotation. Furthermore, Lin occasionally resorted to such cultural substitution strategies as absolute universalization and domestication. It is concluded that on the whole Lin adopted a source-oriented approach to translation when working on Shen Fu's work. This study sheds fresh light on Lin's selection of translation strategies in the early years of his lifelong career as “a native interpreter of Chinese culture for Western readers”. Keywords: Place Names, Chinese Culture, Lin Yutang, Translation Strategies

  11. Lin28a promotes self-renewal and proliferation of dairy goat spermatogonial stem cells (SSCs) through regulation of mTOR and PI3K/AKT.

    Science.gov (United States)

    Ma, Fanglin; Zhou, Zhe; Li, Na; Zheng, Liming; Wu, Chongyang; Niu, Bowen; Tang, Furong; He, Xin; Li, Guangpeng; Hua, Jinlian

    2016-12-12

    Lin28a is a conserved RNA-binding protein that plays an important role in development, pluripotency, stemness maintenance, proliferation and self-renewal. Early studies showed that Lin28a serves as a marker of spermatogonial stem cells (SSCs) and promotes the proliferation capacity of mouse SSCs. However, there is little information about Lin28a in livestock SSCs. In this study, we cloned Capra hircus Lin28a CDS and found that it is evolutionarily conserved. Lin28a is widely expressed in different tissues of Capra hircus, but is expressed at a high level in the testis. Lin28a is specifically located in the cytoplasm of Capra hircus spermatogonial stem cells and may also be a marker of dairy goat spermatogonial stem cells. Lin28a promoted proliferation and maintained the self-renewal of GmGSCs-I-SB in vivo and in vitro. Lin28a-overexpressing GmGSCs-I-SB showed an enhanced proliferation rate, which might be due to increased PCNA expression. Moreover, Lin28a maintained the self-renewal of GmGSCs-I-SB by up-regulating the expression of OCT4, SOX2, GFRA1, PLZF and ETV5. Furthermore, we found that Lin28a may activate the AKT, ERK, and mTOR signaling pathways to promote the proliferation and maintain the self-renewal of GmGSCs-I-SB.

  12. Tissue-specific regulation of the LIM homeobox gene lin-11 during development of the Caenorhabditis elegans egg-laying system.

    Science.gov (United States)

    Gupta, Bhagwati P; Sternberg, Paul W

    2002-07-01

    The egg-laying system of Caenorhabditis elegans hermaphrodites requires development of the vulva and its precise connection with the uterus. This process is regulated by LET-23-mediated epidermal growth factor signaling and LIN-12-mediated lateral signaling pathways. Among the nuclear factors that act downstream of these pathways, the LIM homeobox gene lin-11 plays a major role. lin-11 mutant animals are egg-laying defective because of the abnormalities in vulval lineage and uterine seam-cell formation. However, the mechanisms providing specificity to lin-11 function are not understood. Here, we examine the regulation of lin-11 during development of the egg-laying system. Our results demonstrate that the tissue-specific expression of lin-11 is controlled by two distinct regulatory elements that function as independent modules and together specify a wild-type egg-laying system. A uterine pi lineage module depends on the LIN-12/Notch signaling, while a vulval module depends on the LIN-17-mediated Wnt signaling. These results provide a unique example of the tissue-specific regulation of a LIM homeobox gene by two evolutionarily conserved signaling pathways. Finally, we provide evidence that the regulation of lin-11 by LIN-12/Notch signaling is directly mediated by the Su(H)/CBF1 family member LAG-1.

  13. Structural requirements for the tissue-specific and tissue-general functions of the Caenorhabditis elegans epidermal growth factor LIN-3.

    Science.gov (United States)

    Liu, J; Tzou, P; Hill, R J; Sternberg, P W

    1999-01-01

    Caenorhabditis elegans lin-3 encodes a homolog of the epidermal growth factor (EGF) family of growth factors. LIN-3 is the inductive signal for hermaphrodite vulval differentiation, and it is required for animal viability, hermaphrodite fertility, and the specification of anterior cell fates in the male B cell lineage. We describe the cloning of a lin-3 homolog from C. briggsae, sequence comparison of C. elegans lin-3 with C. briggsae lin-3, and the determination of molecular lesions in alleles of C. elegans lin-3, including three new alleles. We also analyzed the severity of phenotypes caused by the new and existing alleles of lin-3. Correlation of mutant phenotypes and their molecular lesions, as well as sequence comparison between two species, reveal that the EGF motif and the N-terminal portion of the cytoplasmic domain are important for the functions of LIN-3 in all tissues, while the C-terminal portion of the cytoplasmic domain is involved in the tissue-specific functions of lin-3. We discuss how the structure of lin-3 contributes to its functions in multiple developmental processes. PMID:10545457

  14. Lin28a promotes self-renewal and proliferation of dairy goat spermatogonial stem cells (SSCs) through regulation of mTOR and PI3K/AKT

    Science.gov (United States)

    Ma, Fanglin; Zhou, Zhe; Li, Na; Zheng, Liming; Wu, Chongyang; Niu, Bowen; Tang, Furong; He, Xin; Li, Guangpeng; Hua, Jinlian

    2016-01-01

    Lin28a is a conserved RNA-binding protein that plays an important role in development, pluripotency, stemness maintenance, proliferation and self-renewal. Early studies showed that Lin28a serves as a marker of spermatogonial stem cells (SSCs) and promotes the proliferation capacity of mouse SSCs. However, there is little information about Lin28a in livestock SSCs. In this study, we cloned Capra hircus Lin28a CDS and found that it is evolutionarily conserved. Lin28a is widely expressed in different tissues of Capra hircus, but is expressed at a high level in the testis. Lin28a is specifically located in the cytoplasm of Capra hircus spermatogonial stem cells and may also be a marker of dairy goat spermatogonial stem cells. Lin28a promoted proliferation and maintained the self-renewal of GmGSCs-I-SB in vivo and in vitro. Lin28a-overexpressing GmGSCs-I-SB showed an enhanced proliferation rate, which might be due to increased PCNA expression. Moreover, Lin28a maintained the self-renewal of GmGSCs-I-SB by up-regulating the expression of OCT4, SOX2, GFRA1, PLZF and ETV5. Furthermore, we found that Lin28a may activate the AKT, ERK, and mTOR signaling pathways to promote the proliferation and maintain the self-renewal of GmGSCs-I-SB. PMID:27941834

  15. MicroRNA-125b/Lin28 pathway contributes to the mesendodermal fate decision of embryonic stem cells.

    Science.gov (United States)

    Wang, Jia; Cao, Nan; Yuan, Min; Cui, Huijuan; Tang, Yuanjia; Qin, Lianju; Huang, Xinfang; Shen, Nan; Yang, Huang-Tian

    2012-06-10

    MicroRNAs (miRNAs) are important regulators of cell fate decisions, while the miRNAs and their targets in the regulation of stem cell differentiation are largely unidentified. Here we report novel functions of miR-125b/Lin28 axis in the regulation of mouse embryonic stem cell (mESC) lineage specification and cardiomyocyte differentiation. With a MicroRNA Array screen, we identified a number of miRNAs significantly changed during ESC differentiation, among which miR-125b showed a marked reduction during early differentiation. The abundantly expressed miR-125b in undifferentiated mESCs was dramatically downregulated to a level hardly detected during differentiation day 3 to 5, with a concomitant upregulation of Lin28. Ectopically expressing miR-125b did not alter characteristics of undifferentiated mESCs, whereas it impaired the endoderm and mesoderm development, but not the ectoderm, and inhibited cardiomyocyte formation. We further demonstrate that miR-125b targeted the 3'-untranslated region of Lin28 and reduced the abundance of Lin28 at both mRNA and protein levels. Moreover, phenotypes of miR-125b overexpressing cells were mimicked by downregulation of Lin28 and rescued by reintroduction of Lin28. In addition, the impaired cardiogenesis in miR-125b-introduced cells was greatly recovered when mimicking endoderm environment by cultivation with the condition medium from a visceral endoderm-like cell line, END-2. These results reveal that the miR-125b/Lin28 axis is an important regulator of early lineage specification and cardiomyocyte differentiation of ESCs.

  16. LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome.

    Directory of Open Access Journals (Sweden)

    Ayumi Matsumoto

    Full Text Available Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID, low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574-91 264 613 bp, which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.

  17. Molecular Dynamics Simulations for Deciphering the Structural Basis of Recognition of Pre-let-7 miRNAs by LIN28.

    Science.gov (United States)

    Sharma, Chhaya; Mohanty, Debasisa

    2017-02-07

    LIN28 protein inhibits biogenesis of miRNAs belonging to the let-7 family by binding to precursor forms of miRNAs. Overexpression of LIN28 and low levels of let-7 miRNAs are associated with several forms of cancer cells. We have performed multiple explicit solvent molecular dynamics simulations ranging from 200 to 500 ns in length on different isoforms of preE-let-7 in complex with LIN28 and also in isolation to identify structural features and key specificity-determining residues (SDRs) that are important for the inhibitory role of LIN28. Our simulations suggest that a conserved structural feature of the loop regions of preE-let-7 miRNAs is more important for LIN28 recognition than sequence conservation among members of the let-7 family or the presence of the GGAG motif in the 3' region. The loop region consisting of a minimum of five nucleotides helps pre-miRNAs to acquire a conformation ideal for binding to LIN28, but pre-let-7c-2 prefers a conformation with a three-nucleotide loop. Thus, our simulations provide a theoretical rationale for the recent experimental observation of the escape of LIN28-mediated repression by pre-let-7c-2. The essential structural and sequence features highlighted in this study might aid in designing synthetic small molecule inhibitors for modulating LIN28-let-7 interaction in malignant cells. We have also identified crucial SDRs of the LIN28-preE-let-7 complex involving 13 residues of LIN28 and 10 residues of the pre-miRNA. On the basis of the conservation profile of these 13 SDRs, we have identified 10 novel proteins that are not annotated as LIN28 like but are similar in sequence, domain, or fold level to LIN28.

  18. The stardust family protein MPP7 forms a tripartite complex with LIN7 and DLG1 that regulates the stability and localization of DLG1 to cell junctions.

    Science.gov (United States)

    Bohl, Joanna; Brimer, Nicole; Lyons, Charles; Vande Pol, Scott B

    2007-03-30

    MPP7, a previously uncharacterized member of the p55 Stardust family of membrane-associated guanylate kinase (MAGUK) proteins, was found in a tripartite complex with DLG1 and LIN7A or LIN7C. MPP7 dimerizes with all three LIN7 family members (LIN7A, -B, and -C) through interaction of the single L27 domain of LIN7 with the carboxyl-terminal L27 domain of MPP7, thereby stabilizing both proteins. The dimer of MPP7 with LIN7A or LIN7C associates with DLG1 through an interaction requiring the amino-terminal L27 domain of MPP7. The amino-terminal L27 domain of MPP7 is not sufficient for interaction with DLG1 but interacts efficiently only if MPP7 is in a complex with LIN7A or -C. Thus the specificity of interaction of DLG1 with the LIN7-MPP7 complex is determined by L27 interactions with both MPP7 and LIN7. The tripartite complex forms in a ratio of 1:1:1 and localizes to epithelial adherens junctions in a manner dependent upon MPP7. Expression of MPP7 stabilizes DLG1 in an insoluble compartment. Expression of MPP7 deleted of the PDZ or Src homology 3 domain redistributes MPP7, DLG1, and LIN7 out of adherens junctions and into the soluble cytoplasmic fraction without changing the localization of E-cadherin. Thus, the stability and localization of DLG1 to cell-cell junctions are complex functions determined by the expression and association of particular Stardust family members together with particular LIN7 family members.

  19. 集体化导致的农业危机——基于博弈论和多任务分析角度的解读%The Agricultural Crisis Caused by Collectivization: An Examination Based on Game Theory and Multitask Principal- Agent Analyses

    Institute of Scientific and Technical Information of China (English)

    田晴

    2012-01-01

    This paper aims at giving thoughts on collectivism before the establishment of the Household Contract Responsibility System in the early 1980s. First,a review of Dr. Justin Yifu Lin's early paper about game theory analysis as applied to agricultural crisis, "Collectivization and China's Agricultural Crisis in 1959 -1961 " (1990), which points out the flaws of the "bad -weather hypothesis"," the hypothesis of bad policies," and "the hypothesis of the incentive issue in the commune", forms the foundation for this study. Secondly, it shows that the main cause of the crisis is the change in the nature of collectivization from a "repeated game" to a "one - time game. " Lastly,this paper deals with the possibility of the overuse of agricultural tools based on Holm- strom Bengt and Paul Migrom's Muhitask Principal- Agent Analyses (1991).%文章对林毅夫教授的英文文章《集体制与中国1959-1961年的农业危机》(Collee.tivizationand China’s Agricultural Crisisin1959-1961)进行了回顾,阐明了自然灾害理论、不恰当政策理论和监管激励理论在解释1959—1961年三年农业危机时出现的错误,并利用公有化由多次博弈向单次博弈的转变解释了危机产生的真正原因。最后,文章结合本特·霍姆斯特洛姆和保罗·米尔格罗姆关于多任务分析的方法指出了公有化对生产资料不合理使用的可能性。

  20. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

    Science.gov (United States)

    Spence, Tara; Sin-Chan, Patrick; Picard, Daniel; Barszczyk, Mark; Hoss, Katharina; Lu, Mei; Kim, Seung-Ki; Ra, Young-Shin; Nakamura, Hideo; Fangusaro, Jason; Hwang, Eugene; Kiehna, Erin; Toledano, Helen; Wang, Yin; Shi, Qing; Johnston, Donna; Michaud, Jean; La Spina, Milena; Buccoliero, Anna Maria; Adamek, Dariusz; Camelo-Piragua, Sandra; Peter Collins, V; Jones, Chris; Kabbara, Nabil; Jurdi, Nawaf; Varlet, Pascale; Perry, Arie; Scharnhorst, David; Fan, Xing; Muraszko, Karin M; Eberhart, Charles G; Ng, Ho-Keung; Gururangan, Sridharan; Van Meter, Timothy; Remke, Marc; Lafay-Cousin, Lucie; Chan, Jennifer A; Sirachainan, Nongnuch; Pomeroy, Scott L; Clifford, Steven C; Gajjar, Amar; Shago, Mary; Halliday, William; Taylor, Michael D; Grundy, Richard; Lau, Ching C; Phillips, Joanna; Bouffet, Eric; Dirks, Peter B; Hawkins, Cynthia E; Huang, Annie

    2014-08-01

    Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

  1. Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107.

    Directory of Open Access Journals (Sweden)

    Rongyue Teng

    Full Text Available Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28 increased their resistance to the chemo-drugs oxaliplatin (OXA, paclitaxel (PTX, doxorubicin (ADM, and fluorouracil (5-Fu compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance.

  2. Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107.

    Science.gov (United States)

    Teng, Rongyue; Hu, Yan; Zhou, Jichun; Seifer, Benjamin; Chen, Yongxia; Shen, Jianguo; Wang, Linbo

    2015-01-01

    Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28) increased their resistance to the chemo-drugs oxaliplatin (OXA), paclitaxel (PTX), doxorubicin (ADM), and fluorouracil (5-Fu) compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA) was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance.

  3. Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively.

    Science.gov (United States)

    Nowak, Jakub Stanislaw; Hobor, Fruzsina; Downie Ruiz Velasco, Angela; Choudhury, Nila Roy; Heikel, Gregory; Kerr, Alastair; Ramos, Andres; Michlewski, Gracjan

    2017-03-01

    Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3'-5' exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing. © 2017 Nowak et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  4. Musashi 2 contributes to the stemness and chemoresistance of liver cancer stem cells via LIN28A activation.

    Science.gov (United States)

    Fang, Tian; Lv, Hongwei; Wu, Fuquan; Wang, Changzheng; Li, Ting; Lv, Guishuai; Tang, Liang; Guo, Linna; Tang, Shanhua; Cao, Dan; Wu, Mengchao; Yang, Wen; Wang, Hongyang

    2017-01-01

    Accumulating evidence suggests that cancer stem cells (CSCs), a small subset of cancer cells, are responsible for tumor initiation, progression, relapse and metastasis. Musashi 2 (MSI2), a RNA-binding protein, was proposed to be a potent oncogene playing key roles in myeloid leukemia and gastrointestinal malignancies. However, it remains elusive how MSI2 regulates stem cell features in HCC. Herein, we demonstrated that MSI2 was highly expressed in liver CSCs. Overexpression or knockdown of MSI2 altered CSC-related gene expression, self-renewal as well as resistance to chemotherapy in HCC cell lines. In mouse xenograft models, MSI2 could markedly enhance tumorigenicity. Mechanistically, overexpression of MSI2 resulted in the upregulation of Lin28A. Stemness and chemotherapeutic drug resistance induced by MSI2 overexpression were dramatically reduced by Lin28A knockdown. Moreover, MSI2 and LIN28A levels positively correlated with the clinical severity and prognosis in HCC patients. In conclusion, MSI2 might play a crucial role in sustaining stemness and chemoresistance of liver CSCs via LIN28A-dependent manner in HCC. Our findings revealed that MSI2 and Lin28A might be used as potential therapeutic targets for eradicating liver CSCs. Copyright © 2016. Published by Elsevier Ireland Ltd.

  5. Genome packaging in EL and Lin68, two giant phiKZ-like bacteriophages of P. aeruginosa

    Energy Technology Data Exchange (ETDEWEB)

    Sokolova, O.S., E-mail: sokolova@mail.bio.msu.ru [M.V. Lomonosov Moscow State University, Moscow (Russian Federation); A.V. Shoubnikov Institute of Crystallography RAS, Moscow (Russian Federation); Shaburova, O.V. [I.I. Mechnikov Research Institute of Vaccines and Sera, RAMS, Moscow (Russian Federation); Pechnikova, E.V. [A.V. Shoubnikov Institute of Crystallography RAS, Moscow (Russian Federation); Shaytan, A.K. [M.V. Lomonosov Moscow State University, Moscow (Russian Federation); Krylov, S.V. [I.I. Mechnikov Research Institute of Vaccines and Sera, RAMS, Moscow (Russian Federation); Kiselev, N.A. [A.V. Shoubnikov Institute of Crystallography RAS, Moscow (Russian Federation); Krylov, V.N. [I.I. Mechnikov Research Institute of Vaccines and Sera, RAMS, Moscow (Russian Federation)

    2014-11-15

    A unique feature of the Pseudomonas aeruginosa giant phage phiKZ is its way of genome packaging onto a spool-like protein structure, the inner body. Until recently, no similar structures have been detected in other phages. We have studied DNA packaging in P. aeruginosa phages EL and Lin68 using cryo-electron microscopy and revealed the presence of inner bodies. The shape and positioning of the inner body and the density of the DNA packaging in EL are different from those found in phiKZ and Lin68. This internal organization explains how the shorter EL genome is packed into a large EL capsid, which has the same external dimensions as the capsids of phiKZ and Lin68. The similarity in the structural organization in EL and other phiKZ-like phages indicates that EL is phylogenetically related to other phiKZ-like phages, and, despite the lack of detectable DNA homology, EL, phiKZ, and Lin68 descend from a common ancestor. - Highlights: • We performed a comparative structural study of giant P. aeruginosa phages: EL, Lin68 and phiKZ. • We revealed that the inner body is a common feature in giant phages. • The phage genome size correlates with the overall dimensions of the inner body.

  6. The Study on Lin Yutang’s Translation from the Perspective of Aesthetics

    Institute of Scientific and Technical Information of China (English)

    瞿宁

    2013-01-01

    Since the main purposes of translation lies in expressing to the target readers both the message and the aesthetic value of the source text and making the readers ideologically inspired and aesthetically entertained, Lin Yutang conclusively sum up that the aesthetic criteria in translation should be faithfulness, expressiveness and beauty throughout his translation practices. This thesis mainly focus on the aesthetic criteria of Lin’s translation as well as the aesthetic reproduction in his translation which illustrates the unity reached in Lin’s translation in terms of both the aesthetic features and the loyalty to the meaning.

  7. A new approach to control the modified LinVerter for high frequency applications

    DEFF Research Database (Denmark)

    Farhang, Peyman; Mátéfi-Tempfli, Stefan

    2016-01-01

    control perspective, a novel control approach based on bidirectional interface between LTspice and MATLAB is created. In this case, the circuit is modeled in LTspice environment and a Chaos Optimization Algorithm (COA) is coded in MATLAB in order to find out the optimal solution in control process....... In fact, this new approach combines the advantages of LTspice for simulation of different circuit configurations using actual component obtained from manufactures' models with advanced intelligent techniques capabilities from COA in MATLAB. First, the performance of proposed multi-device LinVerter along...

  8. Décoloration d’une huile végétale (huile de lin)

    OpenAIRE

    TAHRAOUI, sarah

    2014-01-01

    aprés anlyses chimique et phsico-chimique de cinq terres décolorante différentes (tonsil EX 096 otimum (allemagne), T.D de maghnia (algérie) , t.d de turquie et T.D d'indonésie,nous avons effectué la décoloration d'une huile de lin par les cinq terres activées en faisant varier plusieurs paéramétre comme le temps d'agitation,la température de l'huile,le type et le pourcentage ed terre utilisée.

  9. [Lin Xue-Jian's experience on treatment of a part of cerebral diseases with scalp acupuncture].

    Science.gov (United States)

    Wang, Hai-Li; Wu, Jiu-Wei

    2005-10-01

    LIN Xue-Jian adopts Chinese traditional acupuncture and moxibustion manipulation methods to stimulate the special area of scalp to treat a part of brain-derived diseases, such as infantile cerebral palsy, nerve deafness, cerebellar ataxia, lacunar cerebral infarction, senile dementia, Parkinson's disease, anxiety, insomnia and central constipation, and so on. Scalp acupuncture can improve ability of blood and oxygen supply for general blood vessels; stimulation of corresponding acupoint area according to symptoms and signs can control condition of disease; and can repair, activate and regenerate the injured, dormancy and aging neurons, so as to dredge nerve network in the brain, hence better therapeutic effect.

  10. LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls

    Directory of Open Access Journals (Sweden)

    Sung Won Park

    2012-10-01

    Full Text Available &lt;B&gt;Purpose:&lt;/B&gt; Single-nucleotide polymorphism (SNP markers within &lt;i&gt;LIN28B&lt;/i&gt; have been reported to be related to the timing of pubertal growth. However, no study has investigated the frequency of genetic markers in girls with precocious puberty (PP or early puberty (EP. This study aimed to determine the frequency of putative genetic markers in girls with PP or EP. &lt;B&gt;Methods:&lt;/B&gt; Genomic DNAs were obtained from 77 and 109 girls that fulfilled the criteria for PP and EP, respectively. The controls in this study were 144 healthy volunteers between 20 and 30 years of age. The haplotypes were reconstructed using 11 SNPs of &lt;i&gt;LIN28B&lt;/i&gt;, and haplotype association analysis was performed. The haplotype frequencies were compared. Differences in the clinical and laboratory parameters were analyzed according to the haplotype dosage. &lt;B&gt;Results:&lt;/B&gt; Eleven SNPs in &lt;i&gt;LIN28B&lt;/i&gt; were all located in a block that was in linkage disequilibrium. The haplotype could be reconstructed using 2 representative SNPs, rs4946651 and rs369065. The AC haplotype was less frequently observed in the PP group than in the controls (0.069 vs. 0.144, &lt;I&gt;P&lt;/I&gt;=0.010. The trend that girls with non-AC haplotypes tended to have earlier puberty onset (&lt;I&gt;P&lt;/I&gt;=0.037 was illustrated even in the EP+PP patient group by Kaplan-Meier analysis. &lt;B&gt;Conclusion:&lt;/B&gt; The results of the present study showed that non-AC haplotypes of &lt;i&gt;LIN28B&lt;/i&gt;had a significant association with PP in girls.

  11. Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin-PI3K-mTOR pathway.

    Science.gov (United States)

    Zhang, Mingming; Sun, Dongdong; Li, Shuang; Pan, Xietian; Zhang, Xiaotian; Zhu, Di; Li, Congye; Zhang, Rongqing; Gao, Erhe; Wang, Haichang

    2015-06-01

    The insulin-PI3K-mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin-sensitivity via insulin-PI3K-mTOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a siRNA (siLin28a) or lin28a cDNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS, improved LV ejection fraction (LVEF), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS, decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre-treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF1R, p-Akt, p-mTOR and p-p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre-treatment abolished the effects of increased p-mTOR and p-p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS, improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin-PI3K-mTOR dependent pathway. © 2015 The Authors. Journal of Cellular and Molecular Medicine

  12. LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program.

    Science.gov (United States)

    Mao, Xing-gang; Hütt-Cabezas, Marianne; Orr, Brent A; Weingart, Melanie; Taylor, Isabella; Rajan, Anand K D; Odia, Yazmin; Kahlert, Ulf; Maciaczyk, Jarek; Nikkhah, Guido; Eberhart, Charles G; Raabe, Eric H

    2013-07-01

    The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs.

  13. An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates.

    Science.gov (United States)

    O'Day, Elizabeth; Le, Minh T N; Imai, Shunsuke; Tan, Shen Mynn; Kirchner, Rory; Arthanari, Haribabu; Hofmann, Oliver; Wagner, Gerhard; Lieberman, Judy

    2015-07-17

    Lin28 is an evolutionarily conserved RNA-binding protein that inhibits processing of pre-let-7 microRNAs (miRNAs) and regulates translation of mRNAs that control developmental timing, pluripotency, metabolism, and tumorigenesis. The RNA features that mediate Lin28 binding to the terminal loops of let-7 pre-miRNAs and to Lin28-responsive elements (LREs) in mRNAs are not well defined. Here we show that Lin28 target datasets are enriched for RNA sequences predicted to contain stable planar structures of 4 guanines known as G-quartets (G4s). The imino NMR spectra of pre-let-7 loops and LREs contain resonances characteristic of G4 hydrogen bonds. These sequences bind to a G4-binding fluorescent dye, N-methyl-mesoporphyrin IX (NMM). Mutations and truncations in the RNA sequence that prevent G4 formation also prevent Lin28 binding. The addition of Lin28 to a pre-let-7 loop or an LRE reduces G4 resonance intensity and NMM binding, suggesting that Lin28 may function to remodel G4s. Further, we show that NMM inhibits Lin28 binding. Incubation of a human embryonal carcinoma cell line with NMM reduces its stem cell traits. In particular it increases mature let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, and inhibits colony formation. Our results suggest a previously unknown structural feature of Lin28 targets and a new strategy for manipulating Lin28 function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates*

    Science.gov (United States)

    O'Day, Elizabeth; Le, Minh T. N.; Imai, Shunsuke; Tan, Shen Mynn; Kirchner, Rory; Arthanari, Haribabu; Hofmann, Oliver; Wagner, Gerhard; Lieberman, Judy

    2015-01-01

    Lin28 is an evolutionarily conserved RNA-binding protein that inhibits processing of pre-let-7 microRNAs (miRNAs) and regulates translation of mRNAs that control developmental timing, pluripotency, metabolism, and tumorigenesis. The RNA features that mediate Lin28 binding to the terminal loops of let-7 pre-miRNAs and to Lin28-responsive elements (LREs) in mRNAs are not well defined. Here we show that Lin28 target datasets are enriched for RNA sequences predicted to contain stable planar structures of 4 guanines known as G-quartets (G4s). The imino NMR spectra of pre-let-7 loops and LREs contain resonances characteristic of G4 hydrogen bonds. These sequences bind to a G4-binding fluorescent dye, N-methyl-mesoporphyrin IX (NMM). Mutations and truncations in the RNA sequence that prevent G4 formation also prevent Lin28 binding. The addition of Lin28 to a pre-let-7 loop or an LRE reduces G4 resonance intensity and NMM binding, suggesting that Lin28 may function to remodel G4s. Further, we show that NMM inhibits Lin28 binding. Incubation of a human embryonal carcinoma cell line with NMM reduces its stem cell traits. In particular it increases mature let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, and inhibits colony formation. Our results suggest a previously unknown structural feature of Lin28 targets and a new strategy for manipulating Lin28 function. PMID:26045559

  15. LIN Dataset

    Data.gov (United States)

    Department of Homeland Security — This data is captured and helps to coordinate technical and scientific testing in the area of Trade Enforcement, WMD, Intellectual Property Rights, and Narcotics...

  16. Estonia's Big Boys' Club / Justin Petrone

    Index Scriptorium Estoniae

    Petrone, Justin, 1979-

    2007-01-01

    Eesti üliõpilasseltside ajaloost, liikmetest ning mõjust Eesti ühiskonnale ja poliitikale. Lähemalt Eesti Üliõpilaste Seltsist (EÜS), selle tekkest, taastamisest Gorbatšovi reformide aastail, liikmeskonnast, suhetest teiste korporatsioonidega. EÜSi liikmete hulka kuulub ka president Toomas Hendrik Ilves. Ajakirjanumbri esikaanel T.H. Ilvese foto

  17. Justin Bieber,His Fun Music World

    Institute of Scientific and Technical Information of China (English)

    罗以宁

    2010-01-01

    贾斯汀·比伯12岁的时候,他参加了他家乡加拿大斯特佛德的歌唱比赛,并获得第二名。他想和他的家人分享这个消息,便把比赛的片段发到YouTube上。随着时间的推移,比伯上传了更多他唱歌时的视频,而他的亲戚并不是唯一去注意的人。5500多万歌迷也登录观看比伯演唱他最喜欢的艺术家的歌曲,包括亚瑟小子、尼欧和史提夫·汪达。

  18. Estonia's Big Boys' Club / Justin Petrone

    Index Scriptorium Estoniae

    Petrone, Justin, 1979-

    2007-01-01

    Eesti üliõpilasseltside ajaloost, liikmetest ning mõjust Eesti ühiskonnale ja poliitikale. Lähemalt Eesti Üliõpilaste Seltsist (EÜS), selle tekkest, taastamisest Gorbatšovi reformide aastail, liikmeskonnast, suhetest teiste korporatsioonidega. EÜSi liikmete hulka kuulub ka president Toomas Hendrik Ilves. Ajakirjanumbri esikaanel T.H. Ilvese foto

  19. Concise Review: LIN28/let-7 Signaling, a Critical Double-Negative Feedback Loop During Pluripotency, Reprogramming, and Tumorigenicity.

    Science.gov (United States)

    Farzaneh, Maryam; Attari, Farnoosh; Khoshnam, Seyed Esmaeil

    2017-08-28

    MicroRNAs (miRNAs) with 20-30 nucleotides have recently emerged as the multidimensional regulators of cell fate decisions. Recent improvement in high-throughput sequencing has highlighted the potential role of LIN28/let-7 regulatory network in several developmental events. It was proposed that this pathway might represent a functional signature in cell proliferation, transition between commitment and pluripotency, and regulation of cancer and tumorigenicity. LIN28/let-7 regulatory pathway is one of the excellent examples of the relationship between an miRNA and mRNAs. This review article highlights the potentials of LIN28/let-7 signaling in gene regulatory pathways during pluripotency, reprogramming, and tumorigenicity.

  20. MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway.

    Science.gov (United States)

    Morgado, Ana L; Rodrigues, Cecília M P; Solá, Susana

    2016-05-01

    MicroRNAs (miRNAs or miRs) regulate several biological functions, including cell fate determination and differentiation. Although miR-145 has already been described to regulate glioma development, its precise role in neurogenesis has never been addressed. miR-145 represses sex-determining region Y-box 2 (Sox2), a core transcription factor of embryonic stem cells (ESCs), to inhibit pluripotency and self-renewal in human ESCs. In addition, the Sox2-Lin28/let-7 signaling pathway regulates proliferation and neurogenesis of neural precursors. In this study, we aimed to investigate the precise role of miR-145 in neural stem cell (NSC) fate decision, and the possible involvement of the Sox2-Lin28/let-7 signaling pathway in miR-145 regulatory network. Our results show for the first time that miR-145 expression significantly increased after induction of mouse NSC differentiation, remaining elevated throughout this process. Forced miR-145 downregulation decreased neuronal markers, namely βIII-tubulin, NeuN, and MAP2. Interestingly, throughout NSC differentiation, protein levels of Sox2 and Lin28, a well-known suppressor of let-7 biogenesis, decreased. Of note, neuronal differentiation also resulted in let-7a and let-7b upregulation. Transfection of NSCs with anti-miR-145, in turn, increased both Sox2 and Lin28 protein levels, while decreasing both let-7a and let-7b. More importantly, Sox2 and Lin28 silencing partially rescued the impairment of neuronal differentiation induced by miR-145 downregulation. In conclusion, our results demonstrate a novel role for miR-145 during NSC differentiation, where miR-145 modulation of Sox2-Lin28/let-7 network is crucial for neurogenesis progression. Stem Cells 2016;34:1386-1395. © 2016 AlphaMed Press.

  1. zePPeLIN: Distributed Path Planning Using an Overhead Camera Network

    Directory of Open Access Journals (Sweden)

    Andreagiovanni Reina

    2014-08-01

    Full Text Available We introduce zePPeLIN, a distributed system designed to address the challenges of path planning in large, cluttered, dynamic environments. The objective is to define a sequence of instructions to precisely move a ground object (e.g., a mobile robot from an initial to a final configuration in an environment. zePPeLIN is based on a set of wirelessly networked overhead cameras. While each camera only covers a limited environment portion, the camera set fully covers the environment through the union of its fields of view. Path planning is performed in a fully distributed and cooperative way, based on potential diffusion over local Voronoi skeletons and local message exchanging. Additionally, the control of the moving object is fully distributed: it receives movement instructions from each camera when it enters that camera’s field of view. The overall task is made particularly challenging by intrinsic errors in the overlap in cameras’ fields of view. We study the performance of the system as a function of these errors, as well as its scalability for the size and density of the camera network. We also propose a few heuristics to improve performance and computational and communication efficiency. The reported results include both extensive simulation experiments and validation using a real camera network planning for a two-robot system.

  2. Genetic variation in LIN28B is associated with the timing of puberty.

    Science.gov (United States)

    Ong, Ken K; Elks, Cathy E; Li, Shengxu; Zhao, Jing Hua; Luan, Jian'an; Andersen, Lars B; Bingham, Sheila A; Brage, Soren; Smith, George Davey; Ekelund, Ulf; Gillson, Christopher J; Glaser, Beate; Golding, Jean; Hardy, Rebecca; Khaw, Kay-Tee; Kuh, Diana; Luben, Robert; Marcus, Michele; McGeehin, Michael A; Ness, Andrew R; Northstone, Kate; Ring, Susan M; Rubin, Carol; Sims, Matthew A; Song, Kijoung; Strachan, David P; Vollenweider, Peter; Waeber, Gerard; Waterworth, Dawn M; Wong, Andrew; Deloukas, Panagiotis; Barroso, Inês; Mooser, Vincent; Loos, Ruth J; Wareham, Nicholas J

    2009-06-01

    The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 × 10(-10); combined P = 3.6 × 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

  3. A Novel Method to Increase LinLog CMOS Sensors’ Performance in High Dynamic Range Scenarios

    Directory of Open Access Journals (Sweden)

    Andrés Iborra

    2011-08-01

    Full Text Available Images from high dynamic range (HDR scenes must be obtained with minimum loss of information. For this purpose it is necessary to take full advantage of the quantification levels provided by the CCD/CMOS image sensor. LinLog CMOS sensors satisfy the above demand by offering an adjustable response curve that combines linear and logarithmic responses. This paper presents a novel method to quickly adjust the parameters that control the response curve of a LinLog CMOS image sensor. We propose to use an Adaptive Proportional-Integral-Derivative controller to adjust the exposure time of the sensor, together with control algorithms based on the saturation level and the entropy of the images. With this method the sensor’s maximum dynamic range (120 dB can be used to acquire good quality images from HDR scenes with fast, automatic adaptation to scene conditions. Adaptation to a new scene is rapid, with a sensor response adjustment of less than eight frames when working in real time video mode. At least 67% of the scene entropy can be retained with this method.

  4. XSHOOTER spectroscopy of the enigmatic planetary nebula Lin49 in the Small Magellanic Cloud

    CERN Document Server

    Otsuka, Masaaki; Leal-Ferreira, M L; Aleman, I; Bernard-Salas, J; Cami, J; Ochsendorf, B; Peeters, E; Scicluna, P

    2016-01-01

    We performed a detailed spectroscopic analysis of the fullerene C60-containing planetary nebula (PN) Lin49 in the Small Magellanic Cloud using XSHOOTER at the ESO VLT and the Spitzer/IRS instruments. We derived nebular abundances for nine elements. We used TLUSTY to derive photospheric parameters for the central star. Lin49 is C-rich and metal-deficient PN (Z~0.0006). The nebular abundances are in good agreement with Asymptotic Giant Branch nucleosynthesis models for stars with initial mass 1.25 Msun and metallicity Z = 0.001. Using the TLUSTY synthetic spectrum of the central star to define the heating and ionising source, we constructed the photoionisation model with CLOUDY that matches the observed spectral energy distribution (SED) and the line fluxes in the UV to far-IR wavelength ranges simultaneously. We could not fit the ~1-5 um SED using a model with 0.005-0.1 um-sized graphite grains and a constant hydrogen density shell owing to the prominent near-IR excess, while at other wavelengths the model fit...

  5. The Overviews on the Research on Lin Gengbai%林庚白研究综述

    Institute of Scientific and Technical Information of China (English)

    闵军

    2011-01-01

    林庚白是民国期间写作旧体诗词的重要诗人。我们大致可以上世纪90年代为界,把林庚白研究分为前后两个时期,前一时期为林庚白研究的奠基期,后一时期为林庚白研究的拓展期。其研究主要从生平事迹的整理和作品研究两个方面展开。我们要继续做好林庚白的作品辑佚、生平事迹、作品研究等工作。%L in Geng -bai is an important poet who writes classical poet during the Republican China. Roughly bounded by the 1990s, the study on Lin Geng - bai can be divided into two periods. The previous period for the study is the foundation period, and the later is the expansion period. The study mainly expands in two ways, the collection of his life biography and works study. We should continue to do the research on Lin Geng-bai, such as his works collection, biography, and works study.

  6. 林则徐与科举%Lin Zexu And Imperial Examination

    Institute of Scientific and Technical Information of China (English)

    张媛媛

    2012-01-01

    Lin Zexu plays a decisive role in modern history, and in the imperial examinations, he also occupies a space. As the examination official, he reformed some of the disadvantages in imperial examination, and made some achievements. By the study of the relationship between Lin Zexu and the imperial examination , we can get some enlightenment.%林则徐是中国近代史上举足轻重的人物,在科举史上同样占有一席之地。在家庭以及社会的影响下林则徐走上了科举之路,并最终金榜题名。作为科考试官他公正衡文、选拔真才,并在江南乡试期间改革科场弊端,取得了一定成效。林则徐提倡“经世致用”,并且贯彻于书院教育和科举考试之中,以期士子能关注社会现实,解决社会实际问题。通过考察林则徐与科举的关系,试图从中得到一些启示。

  7. A Lin28 homologue reprograms differentiated cells to stem cells in the moss Physcomitrella patens

    Science.gov (United States)

    Li, Chen; Sako, Yusuke; Imai, Akihiro; Nishiyama, Tomoaki; Thompson, Kari; Kubo, Minoru; Hiwatashi, Yuji; Kabeya, Yukiko; Karlson, Dale; Wu, Shu-Hsing; Ishikawa, Masaki; Murata, Takashi; Benfey, Philip N.; Sato, Yoshikatsu; Tamada, Yosuke; Hasebe, Mitsuyasu

    2017-01-01

    Both land plants and metazoa have the capacity to reprogram differentiated cells to stem cells. Here we show that the moss Physcomitrella patens Cold-Shock Domain Protein 1 (PpCSP1) regulates reprogramming of differentiated leaf cells to chloronema apical stem cells and shares conserved domains with the induced pluripotent stem cell factor Lin28 in mammals. PpCSP1 accumulates in the reprogramming cells and is maintained throughout the reprogramming process and in the resultant stem cells. Expression of PpCSP1 is negatively regulated by its 3′-untranslated region (3′-UTR). Removal of the 3′-UTR stabilizes PpCSP1 transcripts, results in accumulation of PpCSP1 protein and enhances reprogramming. A quadruple deletion mutant of PpCSP1 and three closely related PpCSP genes exhibits attenuated reprogramming indicating that the PpCSP genes function redundantly in cellular reprogramming. Taken together, these data demonstrate a positive role of PpCSP1 in reprogramming, which is similar to the function of mammalian Lin28. PMID:28128346

  8. Wolbachia induces male-specific mortality in the mosquito Culex pipiens (LIN strain.

    Directory of Open Access Journals (Sweden)

    Jason L Rasgon

    Full Text Available BACKGROUND: Wolbachia are maternally inherited endosymbionts that infect a diverse range of invertebrates, including insects, arachnids, crustaceans and filarial nematodes. Wolbachia are responsible for causing diverse reproductive alterations in their invertebrate hosts that maximize their transmission to the next generation. Evolutionary theory suggests that due to maternal inheritance, Wolbachia should evolve toward mutualism in infected females, but strict maternal inheritance means there is no corresponding force to select for Wolbachia strains that are mutualistic in males. METHODOLOGY/PRINCIPAL FINDINGS: Using cohort life-table analysis, we demonstrate that in the mosquito Culex pipiens (LIN strain, Wolbachia-infected females show no fitness costs due to infection. However, Wolbachia induces up to a 30% reduction in male lifespan. CONCLUSIONS/SIGNIFICANCE: These results indicate that the Wolbachia infection of the Culex pipiens LIN strain is virulent in a sex-specific manner. Under laboratory situations where mosquitoes generally mate at young ages, Wolbachia strains that reduce male survival could evolve by drift because increased mortality in older males is not a significant selective force.

  9. Lin28A enhances chemosensitivity of colon cancer cells to 5-FU by promoting apoptosis in a let-7 independent manner.

    Science.gov (United States)

    Wang, Tianzhen; Han, Peng; He, Yan; Zhao, Ci; Wang, Guangyu; Yang, Weiwei; Shan, Ming; Zhu, Yuanyuan; Yang, Chao; Weng, Mingjiao; Wu, Di; Gao, Lin; Jin, Xiaoming; Wei, Yunwei; Cui, BinBin; Shen, Guomin; Li, Xiaobo

    2016-06-01

    RNA-binding protein Lin28A is frequently over-expressed in human malignant tumors and is associated with tumor advance and poor prognosis. However, the expression pattern and functions of Lin28A in colon cancer are unknown. In this study, we detected the expression of Lin28A in colon cancer patients and tested the effect of Lin28A on the chemotherapeutic sensitivity of colon cancer cells to 5-fluorouracil (5-FU). As expected, we showed that Lin28A is up-regulated in 73.3 % of colon cancer patients. However, to our surprise, we found that oncogenic protein Lin28A-enforced expression in colon cancer cells enhanced the chemosensitivity of cancer cells to 5-FU via promoting the cell apoptosis. Further mechanisms study revealed that the effect of Lin28A increasing chemosensitivity of cancer cells is in a let-7 independent manner, but which is associated with decreasing the expression of DNA damage repair protein H2AX. Conclusively, here we reported an unexpected function of Lin28A, which may shed lights on fully understanding the physiological and pathological roles of this oncogene.

  10. Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer.

    Science.gov (United States)

    Yin, Jun; Zhao, Jian; Hu, Weimin; Yang, Guangping; Yu, Hui; Wang, Ruihao; Wang, Linjing; Zhang, Guoqian; Fu, Wenfan; Dai, Lu; Li, Wanzhen; Liao, Boyu; Zhang, Shuxu

    2017-01-01

    Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.

  11. Efficient method to create integration-free, virus-free, Myc and Lin28-free human induced pluripotent stem cells from adherent cells.

    Science.gov (United States)

    Kamath, Anant; Ternes, Sara; McGowan, Stephen; English, Anthony; Mallampalli, Rama; Moy, Alan B

    2017-08-01

    Nonviral induced pluripotent stem cell (IPSC) reprogramming is not efficient without the oncogenes, Myc and Lin28. We describe a robust Myc and Lin28-free IPSC reprogramming approach using reprogramming molecules. IPSC colony formation was compared in the presence and absence of Myc and Lin28 by the mixture of reprogramming molecules and episomal vectors. While more colonies were observed in cultures transfected with the aforementioned oncogenes, the Myc and Lin28-free method achieved the same reprogramming efficiency as reports that used these oncogenes. Further, all colonies were fully reprogrammed based on expression of SSEA4, even in the absence of Myc and Lin28. This approach satisfies an important regulatory pathway for developing IPSC cell therapies with lower clinical risk.

  12. MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells.

    Science.gov (United States)

    Xu, Min; Bian, Shihui; Li, Jie; He, Junbo; Chen, Hui; Ge, Lu; Jiao, Zhijun; Zhang, Youli; Peng, Wanxin; Du, Fengyi; Mo, Yinyuan; Gong, Aihua

    2016-03-22

    LIN28A aberrant expression contributes to the development of human malignancies. However, the LIN28A expression profile remains to be clarified. Herein, we report that LIN28A expression is directly associated with the methylation status of its two CpG island sites in pancreatic cancer cells. First, Bisulfite sequencing reveals that PANC1 cells possess the higher methylation rate at LIN28A CpG islands compared with SW1990 and PaTu8988 cells. Subsequently, LIN28A expression is increased at both mRNA and protein levels in pancreatic cancer cells treated with 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor. Further Chromatin immunoprecipitation (ChIP) assays indicate that methyl-CpG-binding protein 2 (MeCP2) binds preferentially to the two hypermethylated CpG islands sites at LIN28A promoter compare to MBD3. Expectedly, MeCP2 knockdown transcriptionally activates LIN28A expression in above cells, rather than MBD3 knockdown. Moreover, LIN28A overexpression remarkably improves OCT4, NANOG and SOX2 expression, and the ability of sphere and colony formation, and enhances the capacities of invasion in PaTu8988 and SW1990 cells, whereas LIN28A knockdown significantly inhibits the above malignant behaviors in PANC1 cells. These findings suggest that LIN28A is epigenetically regulated via MeCP2 binding to methylated-CpG islands, and may play a crucial role in pancreatic cancer progression.

  13. Overexpression of Lin28 inhibits the proliferation, migration and cell cycle progression and induces apoptosis of BGC-823 gastric cancer cells.

    Science.gov (United States)

    Song, Hu; Xu, Wei; Song, Jun; Liang, Yong; Fu, Wei; Zhu, Xiao-Cheng; Li, Chao; Peng, Jun-Sheng; Zheng, Jun-Nian

    2015-02-01

    Lin28 plays important roles in the development, maintenance of pluripotency and progression of various types of cancers. Lin28 represses the biogenesis of let-7 microRNAs and is implicated in both development and tumorigenesis. Oncogenic regulation of let-7 microRNAs has been demonstrated in several human malignancies, yet their correlation with Lin28 has not yet been studied in gastric cancer. Therefore, in the present study, we explored the possible mechanisms involved in the effects by Lin28 on the proliferation, migration, cell cycle arrest and apoptosis in gastric cancer cells via alteration of let-7 miRNA. The expression levels of Lin28 and let-7 were detected by real-time PCR in gastric cancer cell lines in vitro. Lin28 was overexpressed in the BGC-823 cells via lentiviral transfection, and let-7 expression was assessed. Cell proliferation and migration capabilities were investigated by MTT and Transwell assays, while cell cycle distribution and the apoptosis rate were detected using flow cytometry. The expression of Lin28 was moderately expressed in the GES cells while underexpressed in the BGC-823, SGC-7901 and HGC-27 cells. Let-7a miRNA was highly expressed in the GES, BGC-823, SGC-7901 and HGC-27 cells. Overexpression of Lin28 was inversely correlated with the downregulated expression of let-7a, and markedly suppressed the proliferation, migration, cell cycle progression and induced apoptosis in the BGC-823 cells. These findings demonstrated that overexpression of Lin28 can suppress the biological behavior of gastric cancer in vitro, and let-7 miRNA may play an important role in the process. We suggest that Lin28 may be a candidate predictor or an anticancer therapeutic target for gastric cancer patients.

  14. Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation.

    Science.gov (United States)

    Choudhury, Nila Roy; Nowak, Jakub S; Zuo, Juan; Rappsilber, Juri; Spoel, Steven H; Michlewski, Gracjan

    2014-11-20

    RNA binding proteins have thousands of cellular RNA targets and often exhibit opposite or passive molecular functions. Lin28a is a conserved RNA binding protein involved in pluripotency and tumorigenesis that was previously shown to trigger TuT4-mediated pre-let-7 uridylation, inhibiting its processing and targeting it for degradation. Surprisingly, despite binding to other pre-microRNAs (pre-miRNAs), only pre-let-7 is efficiently uridylated by TuT4. Thus, we hypothesized the existence of substrate-specific cofactors that stimulate Lin28a-mediated pre-let-7 uridylation or restrict its functionality on non-let-7 pre-miRNAs. Through RNA pull-downs coupled with quantitative mass spectrometry, we identified the E3 ligase Trim25 as an RNA-specific cofactor for Lin28a/TuT4-mediated uridylation. We show that Trim25 binds to the conserved terminal loop (CTL) of pre-let-7 and activates TuT4, allowing for more efficient Lin28a-mediated uridylation. These findings reveal that protein-modifying enzymes, only recently shown to bind RNA, can guide the function of canonical ribonucleoprotein (RNP) complexes in cis, thereby providing an additional level of specificity.

  15. Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation

    Directory of Open Access Journals (Sweden)

    Nila Roy Choudhury

    2014-11-01

    Full Text Available RNA binding proteins have thousands of cellular RNA targets and often exhibit opposite or passive molecular functions. Lin28a is a conserved RNA binding protein involved in pluripotency and tumorigenesis that was previously shown to trigger TuT4-mediated pre-let-7 uridylation, inhibiting its processing and targeting it for degradation. Surprisingly, despite binding to other pre-microRNAs (pre-miRNAs, only pre-let-7 is efficiently uridylated by TuT4. Thus, we hypothesized the existence of substrate-specific cofactors that stimulate Lin28a-mediated pre-let-7 uridylation or restrict its functionality on non-let-7 pre-miRNAs. Through RNA pull-downs coupled with quantitative mass spectrometry, we identified the E3 ligase Trim25 as an RNA-specific cofactor for Lin28a/TuT4-mediated uridylation. We show that Trim25 binds to the conserved terminal loop (CTL of pre-let-7 and activates TuT4, allowing for more efficient Lin28a-mediated uridylation. These findings reveal that protein-modifying enzymes, only recently shown to bind RNA, can guide the function of canonical ribonucleoprotein (RNP complexes in cis, thereby providing an additional level of specificity.

  16. MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit

    Science.gov (United States)

    Li, X; Zhang, J; Gao, L; McClellan, S; Finan, M A; Butler, T W; Owen, L B; Piazza, G A; Xi, Yaguang

    2012-01-01

    MicroRNAs (miRNAs) have attracted attention because of their key regulatory functions in many biological events, including differentiation and tumorigenesis. Recent studies have reported the existence of a reciprocal regulatory loop between the family of let-7 miRNAs and an RNA-binding protein, Lin28, both of which have been documented for their important roles during cell differentiation. Hence, using bipotent K562 human leukemia cells and human CD34+ hematopoietic progenitor cells as research models, we demonstrate that let-7 and Lin28 have contrary roles in megakaryocytic (MK) differentiation with a dynamic balance; expression of miR-181 is capable of effectively repressing Lin28 expression, disrupting the Lin28–let-7 reciprocal regulatory loop, upregulating let-7, and eventually promoting MK differentiation. However, miR-181 lacks a significant effect on hemin-induced erythrocyte differentiation. These results demonstrate that miR-181 can function as a ‘molecular switch' during hematopoietic lineage progression specific to MK differentiation, thus providing insight into future development of miRNA-oriented therapeutics. PMID:21979467

  17. Lin28B promotes Müller glial cell de-differentiation and proliferation in the regenerative rat retinas

    Science.gov (United States)

    Tao, Zui; Zhao, Chen; Jian, Qian; Gillies, Mark; Xu, Haiwei; Yin, Zheng Qin

    2016-01-01

    Retinal regeneration and repair are severely impeded in higher mammalian animals. Although Müller cells can be activated and show some characteristics of progenitor cells when injured or under pathological conditions, they quickly form gliosis scars. Unfortunately, the basic mechanisms that impede retinal regeneration remain unknown. We studied retinas from Royal College of Surgeon (RCS) rats and found that let-7 family molecules, let-7e and let-7i, were significantly overexpressed in Müller cells of degenerative retinas. It demonstrated that down-regulation of the RNA binding protein Lin28B was one of the key factors leading to the overexpression of let-7e and let-7i. Lin28B ectopic expression in the Müller cells suppressed overexpression of let-7e and let-7i, stimulated and mobilized Müller glia de-differentiation, proliferation, promoted neuronal commitment, and inhibited glial fate acquisition of de-differentiated Müller cells. ERG recordings revealed that the amplitudes of a-wave and b-wave were improved significantly after Lin28B was delivered into the subretinal space of RCS rats. In summary, down-regulation of Lin28B as well as up-regulation of let-7e and let-7i may be the main factors that impede Müller cell de-differentiation and proliferation in the retina of RCS rats. PMID:27384999

  18. Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty.

    Science.gov (United States)

    Sangiao-Alvarellos, S; Manfredi-Lozano, M; Ruiz-Pino, F; Navarro, V M; Sánchez-Garrido, M A; Leon, S; Dieguez, C; Cordido, F; Matagne, V; Dissen, G A; Ojeda, S R; Pinilla, L; Tena-Sempere, M

    2013-02-01

    Lin28 and Lin28b are related RNA-binding proteins that inhibit the maturation of miRNAs of the let-7 family and participate in the control of cellular stemness and early embryonic development. Considerable interest has arisen recently concerning other physiological roles of the Lin28/let-7 axis, including its potential involvement in the control of puberty, as suggested by genome-wide association studies and functional genomics. We report herein the expression profiles of Lin28 and let-7 members in the rat hypothalamus during postnatal maturation and in selected models of altered puberty. The expression patterns of c-Myc (upstream positive regulator of Lin28), mir-145 (negative regulator of c-Myc), and mir-132 and mir-9 (putative miRNA repressors of Lin28, predicted by bioinformatic algorithms) were also explored. In male and female rats, Lin28, Lin28b, and c-Myc mRNAs displayed very high hypothalamic expression during the neonatal period, markedly decreased during the infantile-to-juvenile transition and reached minimal levels before/around puberty. A similar puberty-related decline was observed for Lin28b in monkey hypothalamus but not in the rat cortex, suggesting species conservation and tissue specificity. Conversely, let-7a, let-7b, mir-132, and mir-145, but not mir-9, showed opposite expression profiles. Perturbation of brain sex differentiation and puberty, by neonatal treatment with estrogen or androgen, altered the expression ratios of Lin28/let-7 at the time of puberty. Changes in the c-Myc/Lin28b/let-7 pathway were also detected in models of delayed puberty linked to early photoperiod manipulation and, to a lesser extent, postnatal underfeeding or chronic subnutrition. Altogether, our data are the first to document dramatic changes in the expression of the Lin28/let-7 axis in the rat hypothalamus during the postnatal maturation and after different manipulations that disturb puberty, thus suggesting the potential involvement of developmental changes in

  19. QUANTUM INSPIRED PARTICLE SWARM COMBINED WITH LIN-KERNIGHAN-HELSGAUN METHOD TO THE TRAVELING SALESMAN PROBLEM

    Directory of Open Access Journals (Sweden)

    Bruno Avila Leal de Meirelles Herrera

    2015-12-01

    Full Text Available ABSTRACT The Traveling Salesman Problem (TSP is one of the most well-known and studied problems of Operations Research field, more specifically, in the Combinatorial Optimization field. As the TSP is a NP (Non-Deterministic Polynomial time-hard problem, there are several heuristic methods which have been proposed for the past decades in the attempt to solve it the best possible way. The aim of this work is to introduce and to evaluate the performance of some approaches for achieving optimal solution considering some symmetrical and asymmetrical TSP instances, which were taken from the Traveling Salesman Problem Library (TSPLIB. The analyzed approaches were divided into three methods: (i Lin-Kernighan-Helsgaun (LKH algorithm; (ii LKH with initial tour based on uniform distribution; and (iii an hybrid proposal combining Particle Swarm Optimization (PSO with quantum inspired behavior and LKH for local search procedure. The tested algorithms presented promising results in terms of computational cost and solution quality.

  20. Minerals detection for hyperspectral images using adapted linear unmixing: LinMin

    CERN Document Server

    Frederic, Schmidt; Stephane, Le Mouelic

    2014-01-01

    Minerals detection over large volume of spectra is the challenge addressed by current hyperspectral imaging spectrometer in Planetary Science. Instruments such OMEGA (Mars Express), CRISM (Mars Reconnaissance Orbiter), M^{3} (Chandrayaan-1), VIRTIS (Rosetta) and many more, have been producing very large datasets since one decade. We propose here a fast supervised detection algorithm called LinMin, in the framework of linear unmixing, with innovative arrangement in order to treat non-linear cases due to radiative transfer in both atmosphere and surface. We use reference laboratory and synthetic spectral library. Additional spectra are used in order to mimic the effect of Martian aerosols, grain size, and observation geometry discrepancies between reference and observed spectra. The proposed algorithm estimates the uncertainty on mixing coefficient from the uncertainty of observed spectra. Both numerical and observational tests validate the approach. Fast parallel implementation of the best algorithm (IPLS) on ...

  1. Reduction of EMC Emissions in Mixed Signal Integrated Circuits with Embedded LIN Driver

    Directory of Open Access Journals (Sweden)

    P. Hartl

    2016-06-01

    Full Text Available This paper describes several methods for reduction of electromagnetic emissions (EME of mixed signal integrated circuits (IC. The focus is on the impact that a LIN bus communication block has on a complex IC which contains analog blocks, noisy digital block, micro-core (µC and several types of memories. It is used in an automotive environment, where EMC emission reduction is one of the key success factors. Several proposed methods for EME reduction are described and implemented on three test chips. These methods include current consumption reduction, internal on-chip decoupling, ground separation and different linear voltage regulator topologies. Measurement results of several fabricated test chips are shown and discussed.

  2. José Lins do Rego: um guia brasileiro de Israel

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    Glauber Pereira Quintão

    2010-03-01

    Full Text Available Este artigo procura analisar, de forma crítica, o livro de José Lins do Rego, Roteiro de Israel, 1955. Busca-­se destacar duas facetas suplementares: a de um olhar poético e a de uma preocupação ético-política lançados pelo escritor sobre a construção do novo Estado de Israel. Observa-­se também uma relação entre os signos da modernidade e das histórias arcaica judaicas. Para isso, usa-­se o conceito de palimpsesto, de Gerard Genette, e de flâneur, de Walter Benjamim.

  3. XSHOOTER spectroscopy of the enigmatic planetary nebula Lin49 in the Small Magellanic Cloud

    Science.gov (United States)

    Otsuka, Masaaki; Kemper, F.; Leal-Ferreira, M. L.; Aleman, I.; Bernard-Salas, J.; Cami, J.; Ochsendorf, B. B.; Peeters, E.; Scicluna, P.

    2016-10-01

    We performed a detailed spectroscopic analysis of the fullerene C60-containing planetary nebula (PN) Lin49 in the Small Magellanic Cloud (SMC) using XSHOOTER at the European Southern Observatory Very Large Telescope and the Spitzer/Infrared Spectrograph instruments. We derived nebular abundances for nine elements. We used TLUSTY to derive photospheric parameters for the central star. Lin49 is C-rich and metal-deficient PN (Z ˜ 0.0006). The nebular abundances are in good agreement with asymptotic giant branch nucleosynthesis models for stars with initial mass 1.25 M⊙ and metallicity Z = 0.001. Using the TLUSTY synthetic spectrum of the central star to define the heating and ionizing source, we constructed the photoionization model with CLOUDY that matches the observed spectral energy distribution (SED) and the line fluxes in the UV to far-IR wavelength ranges simultaneously. We could not fit the ˜1-5 μm SED using a model with 0.005-0.1-μm-sized graphite grains and a constant hydrogen density shell owing to the prominent near-IR excess, while at other wavelengths the model fits the observed values reasonably well. We argue that the near-IR excess might indicate either (1) the presence of very small particles in the form of small carbon clusters, small graphite sheets, or fullerene precursors, or (2) the presence of a high-density structure surrounding the central star. We found that SMC C60 PNe show a near-IR excess component to lesser or greater degree. This suggests that these C60 PNe might maintain a structure nearby their central star.

  4. LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson's disease model.

    Science.gov (United States)

    Rhee, Yong-Hee; Kim, Tae-Ho; Jo, A-Young; Chang, Mi-Yoon; Park, Chang-Hwan; Kim, Sang-Mi; Song, Jae-Jin; Oh, Sang-Min; Yi, Sang-Hoon; Kim, Hyeon Ho; You, Bo-Hyun; Nam, Jin-Wu; Lee, Sang-Hun

    2016-10-01

    The original properties of tissue-specific stem cells, regardless of their tissue origins, are inevitably altered during in vitro culturing, lessening the clinical and research utility of stem cell cultures. Specifically, neural stem cells derived from the ventral midbrain lose their dopamine neurogenic potential, ventral midbrain-specific phenotypes, and repair capacity during in vitro cell expansion, all of which are critical concerns in using the cultured neural stem cells in therapeutic approaches for Parkinson's disease. In this study, we observed that the culture-dependent changes of neural stem cells derived from the ventral midbrain coincided with loss of RNA-binding protein LIN28A expression. When LIN28A expression was forced and sustained during neural stem cell expansion using an inducible expression-vector system, loss of dopamine neurogenic potential and midbrain phenotypes after long-term culturing was blocked. Furthermore, dopamine neurons that differentiated from neural stem cells exhibited remarkable survival and resistance against toxic insults. The observed effects were not due to a direct action of LIN28A on the differentiated dopamine neurons, but rather its action on precursor neural stem cells as exogene expression was switched off in the differentiating/differentiated cultures. Remarkable and reproducible behavioural recovery was shown in all Parkinson's disease rats grafted with neural stem cells expanded with LIN28A expression, along with extensive engraftment of dopamine neurons expressing mature neuronal and midbrain-specific markers. These findings suggest that LIN28A expression during stem cell expansion could be used to prepare therapeutically competent donor cells. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. [Analysis of acid rain characteristics of Lin'an Regional Background Station using long-term observation data].

    Science.gov (United States)

    Li, Zheng-Quan; Ma, Hao; Mao, Yu-Ding; Feng, Tao

    2014-02-01

    Using long-term observation data of acid rain at Lin'an Regional Background Station (Lin'an RBS), this paper studied the interannual and monthly variations of acid rain, the reasons for the variations, and the relationships between acid rain and meteorological factors. The results showed that interannual variation of acid rain at Lin'an RBS had a general increasing trend in which there were two obvious intensifying processes and two distinct weakening processes, during the period ranging from 1985 to 2012. In last two decades, the monthly variation of acid rain at Lin'an RBS indicated that rain acidity and frequency of severe acid rain were increasing but the frequency of weak acid rain was decreasing when moving towards bilateral side months of July. Acid rain occurrence was affected by rainfall intensity, wind speed and wind direction. High frequency of severe acid rain and low frequency of weak acid rain were on days with drizzle, but high frequency of weak acid rain and low frequency of severe acid rain occurred on rainstorm days. With wind speed upgrading, the frequency of acid rain and the proportion of severe acid rain were declining, the pH value of precipitation was reducing too. Another character is that daily dominant wind direction of weak acid rain majorly converged in S-W section ,however that of severe acid rain was more likely distributed in N-E section. The monthly variation of acid rain at Lin'an RBS was mainly attributed to precipitation variation, the increasing and decreasing of monthly incoming wind from SSE-WSW and NWN-ENE sections of wind direction. The interannual variation of acid rain could be due to the effects of energy consumption raising and significant green policies conducted in Zhejiang, Jiangsu and Shanghai.

  6. SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs.

    Science.gov (United States)

    Kim, Seung-Kyoon; Lee, Hosuk; Han, Kyumin; Kim, Sang Cheol; Choi, Yoonjung; Park, Sang-Wook; Bak, Geunu; Lee, Younghoon; Choi, Jung Kyoon; Kim, Tae-Kyung; Han, Yong-Mahn; Lee, Daeyoup

    2014-12-04

    LIN28-mediated processing of the microRNA (miRNA) let-7 has emerged as a multilevel program that controls self-renewal in embryonic stem cells. LIN28A is believed to act primarily in the cytoplasm together with TUT4/7 to prevent final maturation of let-7 by Dicer, whereas LIN28B has been suggested to preferentially act on nuclear processing of let-7. Here, we find that SET7/9 monomethylation in a putative nucleolar localization region of LIN28A increases its nuclear retention and protein stability. In the nucleoli of human embryonic stem cells, methylated LIN28A sequesters pri-let-7 and blocks its processing independently of TUT4/7. The nuclear form of LIN28A regulates transcriptional changes in MYC-pathway targets, thereby maintaining stemness programs and inhibiting expression of early lineage-specific markers. These findings provide insight into the molecular mechanism underlying the posttranslational methylation of nuclear LIN28A and its ability to modulate pluripotency by repressing let-7 miRNA expression in human embryonic stem cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Erythroid-Specific Expression of LIN28A Is Sufficient for Robust Gamma-Globin Gene and Protein Expression in Adult Erythroblasts.

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    Y Terry Lee

    Full Text Available Increasing fetal hemoglobin (HbF levels in adult humans remains an active area in hematologic research. Here we explored erythroid-specific LIN28A expression for its effect in regulating gamma-globin gene expression and HbF levels in cultured adult erythroblasts. For this purpose, lentiviral transduction vectors were produced with LIN28A expression driven by erythroid-specific gene promoter regions of the human KLF1 or SPTA1 genes. Transgene expression of LIN28A with a linked puromycin resistance marker was restricted to the erythroid lineage as demonstrated by selective survival of erythroid colonies (greater than 95% of all colonies. Erythroblast LIN28A over-expression (LIN28A-OE did not significantly affect proliferation or inhibit differentiation. Greater than 70% suppression of total let-7 microRNA levels was confirmed in LIN28A-OE cells. Increases in gamma-globin mRNA and protein expression with HbF levels reaching 30-40% were achieved. These data suggest that erythroblast targeting of LIN28A expression is sufficient for increasing fetal hemoglobin expression in adult human erythroblasts.

  8. Erythroid-Specific Expression of LIN28A Is Sufficient for Robust Gamma-Globin Gene and Protein Expression in Adult Erythroblasts.

    Science.gov (United States)

    Lee, Y Terry; de Vasconcellos, Jaira F; Byrnes, Colleen; Kaushal, Megha; Rabel, Antoinette; Tumburu, Laxminath; Allwardt, Joshua M; Miller, Jeffery L

    2015-01-01

    Increasing fetal hemoglobin (HbF) levels in adult humans remains an active area in hematologic research. Here we explored erythroid-specific LIN28A expression for its effect in regulating gamma-globin gene expression and HbF levels in cultured adult erythroblasts. For this purpose, lentiviral transduction vectors were produced with LIN28A expression driven by erythroid-specific gene promoter regions of the human KLF1 or SPTA1 genes. Transgene expression of LIN28A with a linked puromycin resistance marker was restricted to the erythroid lineage as demonstrated by selective survival of erythroid colonies (greater than 95% of all colonies). Erythroblast LIN28A over-expression (LIN28A-OE) did not significantly affect proliferation or inhibit differentiation. Greater than 70% suppression of total let-7 microRNA levels was confirmed in LIN28A-OE cells. Increases in gamma-globin mRNA and protein expression with HbF levels reaching 30-40% were achieved. These data suggest that erythroblast targeting of LIN28A expression is sufficient for increasing fetal hemoglobin expression in adult human erythroblasts.

  9. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells.

    Science.gov (United States)

    Peng, Shuping; Chen, Ling-Ling; Lei, Xin-Xiang; Yang, Li; Lin, Haifan; Carmichael, Gordon G; Huang, Yingqun

    2011-03-01

    Lin28 inhibits the expression of let-7 microRNAs but also exhibits let-7-independent functions. Using immunoprecipitation and deep sequencing, we show here that Lin28 preferentially associates with a small subset of cellular mRNAs. Of particular interest are those for ribosomal proteins and metabolic enzymes, the expression levels of which are known to be coupled to cell growth and survival. Polysome profiling and reporter analyses suggest that Lin28 stimulates the translation of many or most of these targets. Moreover, Lin28-responsive elements were found within the coding regions of all target genes tested. Finally, a mutant Lin28 that still binds RNA but fails to interact with RNA helicase A (RHA), acts as a dominant-negative inhibitor of Lin28-dependent stimulation of translation. We suggest that Lin28, working in concert with RHA, enhances the translation of genes important for the growth and survival of human embryonic stem cells. Copyright © 2011 AlphaMed Press.

  10. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target.

    Science.gov (United States)

    Weingart, Melanie F; Roth, Jacquelyn J; Hutt-Cabezas, Marianne; Busse, Tracy M; Kaur, Harpreet; Price, Antoinette; Maynard, Rachael; Rubens, Jeffrey; Taylor, Isabella; Mao, Xing-Gang; Xu, Jingying; Kuwahara, Yasumichi; Allen, Sariah J; Erdreich-Epstein, Anat; Weissman, Bernard E; Orr, Brent A; Eberhart, Charles G; Biegel, Jaclyn A; Raabe, Eric H

    2015-02-20

    Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.

  11. Activation of the Lin28/let-7 Axis by Loss of ESE3/EHF Promotes a Tumorigenic and Stem-like Phenotype in Prostate Cancer.

    Science.gov (United States)

    Albino, Domenico; Civenni, Gianluca; Dallavalle, Cecilia; Roos, Martina; Jahns, Hartmut; Curti, Laura; Rossi, Simona; Pinton, Sandra; D'Ambrosio, Gioacchino; Sessa, Fausto; Hall, Jonathan; Catapano, Carlo V; Carbone, Giuseppina M

    2016-06-15

    Although cancer stem-like cells (CSC) are thought to be the most tumorigenic, metastatic, and therapy-resistant cell subpopulation within human tumors, current therapies target bulk tumor cells while tending to spare CSC. In seeking to understand mechanisms needed to acquire and maintain a CSC phenotype in prostate cancer, we investigated connections between the ETS transcription factor ESE3/EHF, the Lin28/let-7 microRNA axis, and the CSC subpopulation in this malignancy. In normal cells, we found that ESE3/EHF bound and repressed promoters for the Lin28A and Lin28B genes while activating transcription and maturation of the let-7 microRNAs. In cancer cells, reduced expression of ESE3/EHF upregulated Lin28A and Lin28B and downregulated the let-7 microRNAs. Notably, we found that deregulation of the Lin28/let-7 axis with reduced production of let-7 microRNAs was critical for cell transformation and expansion of prostate CSC. Moreover, targeting Lin28A/Lin28B in cell lines and tumor xenografts mimicked the effects of ESE3/EHF and restrained tumor-initiating and self-renewal properties of prostate CSC both in vitro and in vivo These results establish that tight control by ESE3/EHF over the Lin28/let-7 axis is a critical barrier to malignant transformation, and they also suggest new strategies to antagonize CSC in human prostate cancer for therapeutic purposes. Cancer Res; 76(12); 3629-43. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Expression and interdependencies of pluripotency factors LIN28, OCT3/4, NANOG and SOX2 in human testicular germ cells and tumours of the testis.

    Science.gov (United States)

    Gillis, A J M; Stoop, H; Biermann, K; van Gurp, R J H L M; Swartzman, E; Cribbes, S; Ferlinz, A; Shannon, M; Oosterhuis, J W; Looijenga, L H J

    2011-08-01

    OCT3/4, NANOG, SOX2 and, most recently, LIN28 have been identified as key regulators of pluripotency in mammalian embryonic and induced stem cells, and are proven to be crucial for generation of the mouse germ-cell lineage. These factors are a hallmark of certain histological types of germ-cell tumours (GCTs). Here, we report novel information on the temporal and spatial expression pattern of LIN28 during normal human male germ-cell development as well as various types of GCTs. To investigate LIN28 expression, immunohistochemical analyses and quantitative proximity ligation assay-based TaqMan protein assays were applied on snap-frozen and formalin-fixed, paraffin-embedded samples as well as representative cell lines. LIN28 was found in primordial germ cells, gonocytes and pre-spermatogonia, in contrast to OCT3/4 and NANOG, which were found only in the first two stages. LIN28 was also found in all precursor lesions (carcinoma in situ and gonadoblastoma) of type II GCTs, as well as the invasive components seminoma and the non-seminomatous elements embryonal carcinoma and yolk sac tumour. Choriocarcinoma showed a heterogeneous pattern, while teratomas and spermatocytic seminomas (type III GCTs) were negative. This expression pattern suggests that LIN28 is associated with malignant behaviour of type II GCTs. Cell line experiments involving siRNA knockdown of LIN28, OCT3/4 and SOX2 showed that LIN28 plays a role in the maintenance of the undifferentiated state of both seminoma and embryonal carcinoma, closely linked to, and likely upstream of OCT3/4 and NANOG. In conclusion, LIN28 regulates the differentiation status of seminoma and embryonal carcinoma and is likely to play a related role in normal human germ-cell development. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

  13. Analysis of a lin-42/period Null Allele Implicates All Three Isoforms in Regulation of Caenorhabditis elegans Molting and Developmental Timing

    Science.gov (United States)

    Edelman, Theresa L. B.; McCulloch, Katherine A.; Barr, Angela; Frøkjær-Jensen, Christian; Jorgensen, Erik M.; Rougvie, Ann E.

    2016-01-01

    The Caenorhabditis elegans heterochronic gene pathway regulates the relative timing of events during postembryonic development. lin-42, the worm homolog of the circadian clock gene, period, is a critical element of this pathway. lin-42 function has been defined by a set of hypomorphic alleles that cause precocious phenotypes, in which later developmental events, such as the terminal differentiation of hypodermal cells, occur too early. A subset of alleles also reveals a significant role for lin-42 in molting; larval stages are lengthened and ecdysis often fails in these mutant animals. lin-42 is a complex locus, encoding overlapping and nonoverlapping isoforms. Although existing alleles that affect subsets of isoforms have illuminated important and distinct roles for this gene in developmental timing, molting, and the decision to enter the alternative dauer state, it is essential to have a null allele to understand all of the roles of lin-42 and its individual isoforms. To remedy this problem and discover the null phenotype, we engineered an allele that deletes the entire lin-42 protein-coding region. lin-42 null mutants are homozygously viable, but have more severe phenotypes than observed in previously characterized hypomorphic alleles. We also provide additional evidence for this conclusion by using the null allele as a base for reintroducing different isoforms, showing that each isoform can provide heterochronic and molting pathway activities. Transcript levels of the nonoverlapping isoforms appear to be under coordinate temporal regulation, despite being driven by independent promoters. The lin-42 null allele will continue to be an important tool for dissecting the functions of lin-42 in molting and developmental timing. PMID:27729432

  14. Analysis of a lin-42/period Null Allele Implicates All Three Isoforms in Regulation of Caenorhabditis elegans Molting and Developmental Timing.

    Science.gov (United States)

    Edelman, Theresa L B; McCulloch, Katherine A; Barr, Angela; Frøkjær-Jensen, Christian; Jorgensen, Erik M; Rougvie, Ann E

    2016-12-07

    The Caenorhabditis elegans heterochronic gene pathway regulates the relative timing of events during postembryonic development. lin-42, the worm homolog of the circadian clock gene, period, is a critical element of this pathway. lin-42 function has been defined by a set of hypomorphic alleles that cause precocious phenotypes, in which later developmental events, such as the terminal differentiation of hypodermal cells, occur too early. A subset of alleles also reveals a significant role for lin-42 in molting; larval stages are lengthened and ecdysis often fails in these mutant animals. lin-42 is a complex locus, encoding overlapping and nonoverlapping isoforms. Although existing alleles that affect subsets of isoforms have illuminated important and distinct roles for this gene in developmental timing, molting, and the decision to enter the alternative dauer state, it is essential to have a null allele to understand all of the roles of lin-42 and its individual isoforms. To remedy this problem and discover the null phenotype, we engineered an allele that deletes the entire lin-42 protein-coding region. lin-42 null mutants are homozygously viable, but have more severe phenotypes than observed in previously characterized hypomorphic alleles. We also provide additional evidence for this conclusion by using the null allele as a base for reintroducing different isoforms, showing that each isoform can provide heterochronic and molting pathway activities. Transcript levels of the nonoverlapping isoforms appear to be under coordinate temporal regulation, despite being driven by independent promoters. The lin-42 null allele will continue to be an important tool for dissecting the functions of lin-42 in molting and developmental timing.

  15. Lin28a protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions.

    Directory of Open Access Journals (Sweden)

    Mingming Zhang

    Full Text Available The aim of the present study was to investigate the role of Lin28a in protecting against hypoxia/reoxygenation (H/R-induced cardiomyocytes apoptosis under high glucose/high fat (HG/HF conditions.Primary cardiomyocytes which were isolated from neonatal mouse were randomized to be treated with lentivirus carrying Lin28a siRNA, Lin28acDNA 72 h before H/R (9 h/2 h. Cardiomyocytes biomarkers release (LDH and CK, cardiomyocytes apoptosis, mitochondria biogenesis and morphology, intracellular reactive oxygen species (ROS production, ATP content and inflammatory cytokines levels after H/R injury in high glucose/high fat conditions were compared between groups. The target proteins of Lin28a were examined by western blot analysis.Our results revealed that Lin28a cDNA transfection (overexpression significantly inhibited cardiomyocyte apoptotic index, improved mitochondria biogenesis, increased ATP production and reduced ROS production as compared with the H/R group in HG/HF conditions. Lin28a siRNA transfection (knockdown rendered the cardiomyocytes more susceptible to H/R injury as evidenced by increased apoptotic index, impaired mitochondrial biogenesis, decreased ATP production and increased ROS level. Interestingly, these effects of Lin28a were blocked by pretreatment with the PI3K inhibitor wortmannin. Lin28a overexpression increased, while Lin28a knockdown inhibited IGF1R, Nrf-1, Tfam, p-IRS-1, p-Akt, p-mTOR, p-p70s6k, p-AMPK expression levels after H/R injury in HG/HF conditions. Moreover, pretreatment with wortmannin abolished the effects of Lin28a on the expression levels of p-AKT, p-mTOR, p-p70s6k, p-AMPK.The present results suggest that Lin28a inhibits cardiomyocytes apoptosis by enhancing mitochondrial biogenesis and function under high glucose/high fat conditions. The mechanism responsible for the effects of Lin28a is associated with the PI3K/Akt dependent pathway.

  16. Lin28a protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions.

    Science.gov (United States)

    Zhang, Mingming; Niu, Xiaolin; Hu, Jianqiang; Yuan, Yuan; Sun, Shuhong; Wang, Jiaxing; Yu, Wenjun; Wang, Chen; Sun, Dongdong; Wang, Haichang

    2014-01-01

    The aim of the present study was to investigate the role of Lin28a in protecting against hypoxia/reoxygenation (H/R)-induced cardiomyocytes apoptosis under high glucose/high fat (HG/HF) conditions. Primary cardiomyocytes which were isolated from neonatal mouse were randomized to be treated with lentivirus carrying Lin28a siRNA, Lin28acDNA 72 h before H/R (9 h/2 h). Cardiomyocytes biomarkers release (LDH and CK), cardiomyocytes apoptosis, mitochondria biogenesis and morphology, intracellular reactive oxygen species (ROS) production, ATP content and inflammatory cytokines levels after H/R injury in high glucose/high fat conditions were compared between groups. The target proteins of Lin28a were examined by western blot analysis. Our results revealed that Lin28a cDNA transfection (overexpression) significantly inhibited cardiomyocyte apoptotic index, improved mitochondria biogenesis, increased ATP production and reduced ROS production as compared with the H/R group in HG/HF conditions. Lin28a siRNA transfection (knockdown) rendered the cardiomyocytes more susceptible to H/R injury as evidenced by increased apoptotic index, impaired mitochondrial biogenesis, decreased ATP production and increased ROS level. Interestingly, these effects of Lin28a were blocked by pretreatment with the PI3K inhibitor wortmannin. Lin28a overexpression increased, while Lin28a knockdown inhibited IGF1R, Nrf-1, Tfam, p-IRS-1, p-Akt, p-mTOR, p-p70s6k, p-AMPK expression levels after H/R injury in HG/HF conditions. Moreover, pretreatment with wortmannin abolished the effects of Lin28a on the expression levels of p-AKT, p-mTOR, p-p70s6k, p-AMPK. The present results suggest that Lin28a inhibits cardiomyocytes apoptosis by enhancing mitochondrial biogenesis and function under high glucose/high fat conditions. The mechanism responsible for the effects of Lin28a is associated with the PI3K/Akt dependent pathway.

  17. LIN28 expression in malignant germ cell tumors down-regulates let-7 and increases oncogene levels

    Science.gov (United States)

    Murray, Matthew J.; Saini, Harpreet K.; Siegler, Charlotte A.; Hanning, Jennifer E.; Barker, Emily M.; van Dongen, Stijn; Ward, Dawn M.; Raby, Katie L.; Groves, Ian J.; Scarpini, Cinzia G.; Pett, Mark R.; Thornton, Claire M.; Enright, Anton J.; Nicholson, James C.; Coleman, Nicholas

    2013-01-01

    Despite their clinico-pathologic heterogeneity, malignant germ-cell-tumors (GCTs) share molecular abnormalities that are likely to be functionally important. In this study, we investigated the potential significance of down-regulation of the let-7 family of tumor-suppressor microRNAs in malignant-GCTs. Microarray results from pediatric and adult samples (n=45) showed that LIN28, the negative-regulator of let-7 biogenesis, was abundant in malignant-GCTs, regardless of patient age, tumor site or histologic subtype. Indeed, a strong negative-correlation existed between LIN28 and let-7 levels in specimens with matched datasets. Low let-7 levels were biologically significant, since the sequence complementary to the 2-7nt common let-7 seed ‘GAGGUA’ was enriched in the 3′untranslated regions of mRNAs up-regulated in pediatric and adult malignant-GCTs, compared with normal gonads (a mixture of germ cells and somatic cells). We identified 27 mRNA targets of let-7 that were up-regulated in malignant-GCT cells, confirming significant negative-correlations with let-7 levels. Among 16 mRNAs examined in a largely independent set of specimens by qRT-PCR, we defined negative-associations with let-7e levels for six oncogenes, including MYCN, AURKB, CCNF, RRM2, MKI67 and C12orf5 (when including normal control tissues). Importantly, LIN28 depletion in malignant-GCT cells restored let-7 levels and repressed all of these oncogenic let-7 mRNA targets, with LIN28 levels correlating with cell proliferation and MYCN levels. Conversely, ectopic expression of let-7e was sufficient to reduce proliferation and down-regulate MYCN, AURKB and LIN28, the latter via a double-negative feedback loop. We concluded that the LIN28/let-7 pathway has a critical pathobiological role in malignant-GCTs and therefore offers a promising target for therapeutic intervention. PMID:23774216

  18. Lin28B Gene Expression and its Role in the Onset of Puberty of Sheep%Lin28B基因表达与绵羊初情期启动的关系研究

    Institute of Scientific and Technical Information of China (English)

    卢萍平; 邢凤; 刘博丹; 梁志鹏

    2014-01-01

    初情期是家畜从不能繁殖到获得繁殖能力的标志,是雌性动物发育过程中的一个关键阶段。研究以性早熟的多浪羊和性晚熟的和田羊为研究对象,对其 L in28B 基因外显子3进行克隆,采用 Real-time PCR 技术分析 Lin28B 基因在多浪羊和和田羊幼年期、初情期下丘脑、卵巢中表达变化,结果显示多浪羊和和田羊 L in28B 基因外显子3序列相同,多浪羊下丘脑和卵巢中 L in28B 基因 mRNA 表达量在初情期时低于幼年期( P <0.05);和田羊卵巢L in28B 基因 mRNA 表达量在初情期时低于幼年期(P<0.05)。研究结果表明,L in28B 基因表达下调与初情期启动呈正相关,该研究对于揭示 L in28B 基因在绵羊初情期启动中的作用及机制提供了科学依据。%Puberty of animals marked their fertility and is a key stage in female animal development . Precocious sheep breed ,Duolang sheep ,and late-maturing sheep breed ,Hetian sheep were selected as sub-jects in the study ,the exon 3 of Lin28B gene of the selected animals were cloned ,and the real-time PCR technology was used to examine the mRNA expression level of Lin28B gene in the hypothalamus and ovary of juvenile stage and pubertal stage .The results showed the sequences alignment of Lin28B exons 3 of Duo-lang sheep and Hetian sheep were the same ;the expression level of Lin28B gene in the hypothalamus and ovary were significantly lower than that in juvenlie period of Duolang sheep (P< 0 .05) ,the expression lev-el of Lin28B gene in the ovary was significantly lower than that in the juvenlie period of Hetian sheep (P<0 .05) .The results indicated that the down-regulated expression of Lin28B gene was positively correlated with the onset of puberty in sheep .The study can help to provide a scientific basis for revealing the effect and mechanism of Lin28B gene in the onset of puberty in sheep .

  19. A role for the malignant brain tumour (MBT domain protein LIN-61 in DNA double-strand break repair by homologous recombination.

    Directory of Open Access Journals (Sweden)

    Nicholas M Johnson

    Full Text Available Malignant brain tumour (MBT domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR for the repair of DNA double-strand breaks (DSBs. lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT-deficient tumours may also have defective DSB repair.

  20. RNA-binding protein LIN28 is a marker for primary extragonadal germ cell tumors: an immunohistochemical study of 131 cases.

    Science.gov (United States)

    Cao, Dengfeng; Liu, Aijun; Wang, Fenghua; Allan, Robert W; Mei, Kaiyong; Peng, Yan; Du, Jun; Guo, Shuangping; Abel, Ty W; Lane, Zhaoli; Ma, Joe; Rodriguez, Maria; Akhi, Shirin; Dehiya, Neha; Li, Jianping

    2011-02-01

    LIN28 has been shown to have an important role in primordial germ cell development and malignant transformation of germ cells in mouse. In this study, we examined the immunohistochemical profile of LIN28 in 131 primary human extragonadal germ cell tumors (central nervous system (CNS) 76, mediastinum 17, sacrococcygeal region 30, pelvis 3, vagina 2, liver 1, omentum 1, and retroperitoneum 1), including the following tumors and/or components: 57 seminomas/germinomas, 10 embryonal carcinomas, 74 yolk sac tumors, 6 choriocarcinomas, 15 mature, and 13 immature teratomas. We compared LIN28 with SALL4 to assess its diagnostic value. To determine its specificity, we examined LIN28 in 406 extragonadal-non-germ cell tumors (103 carcinomas, 91 sarcomas, 9 melanomas, 12 mesotheliomas, 83 lymphomas, 9 plasmacytomas, 82 CNS tumors, and 17 thymic epithelial tumors). The staining was semi-quantitatively scored as 0 (no cell stained), 1+ (0-30%), 2+ (31-60%), 3+ (61-90%), and 4+ (>90%). LIN28 staining was seen in all seminomas/germinomas (3+ in 1 and 4+ in 56), embryonal carcinomas (4+ in all 10), and yolk sac tumors (3+ in 3 and 4+ in 71). Variable LIN28 staining was seen in 5 of 6 choriocarcinomas (1+ to 4+), 8 of 13 immature teratomas (1+ to 2+ in immature elements), and in 1 of 15 mature teratomas (1+). Only 11 of 406 non-germ cell tumors showed 1+ LIN28 staining. Therefore, LIN28 is a sensitive (100% sensitivity) marker for primary extragonadal seminomas/germinomas, embryonal carcinomas, and yolk sac tumors with high specificity. Compared with SALL4, LIN28 demonstrated a similar level of diagnostic sensitivity for seminomas/germinomas and embryonal carcinomas. For primary extragonadal yolk sac tumors, although SALL4 stained all tumors (1+ in 1, 2+ in 2, 3+ in 10, and 4+ in 61), LIN28 stained more tumor cells (mean 95 vs 90%, P = 0.03) and was therefore more sensitive. For primary extragonadal yolk sac tumors, combining LIN28 and SALL4 can achieve a higher diagnostic

  1. Germ cell loss is associated with fading Lin28a expression in a mouse model for Klinefelter's syndrome.

    Science.gov (United States)

    Werler, Steffi; Demond, Hannah; Damm, Oliver S; Ehmcke, Jens; Middendorff, Ralf; Gromoll, Jörg; Wistuba, Joachim

    2014-03-01

    Klinefelter's syndrome is a male sex-chromosomal disorder (47,XXY), causing hypogonadism, cognitive and metabolic deficits. The majority of patients are infertile due to complete germ cell loss after puberty. As the depletion occurs during development, the possibilities to study the underlying causes in humans are limited. In this study, we used the 41,XX(Y*) mouse model to characterise the germ line postnatally. We examined marker expression of testicular cells focusing on the spermatogonial stem cells (SSCs) and found that the number of germ cells was approximately reduced fivefold at day 1pp in the 41,XX(Y*) mice, indicating the loss to start prenatally. Concurrently, immunohistochemical SSC markers LIN28A and PGP9.5 also showed decreased expression on day 1pp in the 41,XX(Y*) mice (48.5 and 38.9% of all germ cells were positive), which dropped to 7.8 and 7.3% on 3dpp, and were no longer detectable on days 5 and 10pp respectively. The differences in PCNA-positive proliferating cells in XY* and XX(Y*) mice dramatically increased towards day 10pp. The mRNA expression of the germ cell markers Lin28a (Lin28), Pou5f1 (Oct4), Utf1, Ddx4 (Vasa), Dazl, and Fapb1 (Sycp3) was reduced and the Lin28a regulating miRNAs were deregulated in the 41,XX(Y*) mice. We suggest a model for the course of germ cell loss starting during the intrauterine period. Neonatally, SSC marker expression by the already lowered number of spermatogonia is reduced and continues fading during the first postnatal week, indicating the surviving cells of the SSC population to be disturbed in their stem cell characteristics. Subsequently, the entire germ line is then generally lost when entering meiosis.

  2. Re-programming of C. elegans male epidermal precursor fates by Wnt, Hox, and LIN-12/Notch activities.

    Science.gov (United States)

    Yu, Hui; Seah, Adeline; Sternberg, Paul W

    2010-09-01

    In Caenorhabditiselegans males, different subsets of ventral epidermal precursor (Pn.p) cells adopt distinct fates in a position-specific manner: three posterior cells, P(9-11).p, comprise the hook sensillum competence group (HCG) with three potential fates (1 degrees , 2 degrees , or 3 degrees ), while eight anterior cells, P(1-8).p, fuse with the hyp7 epidermal syncytium. Here we show that activation of the canonical BAR-1 beta-catenin pathway of Wnt signaling alters the competence of P(3-8).p and specifies ectopic HCG-like fates. This fate transformation requires the Hox gene mab-5. In addition, misexpression of mab-5 in P(1-8).p is sufficient to establish HCG competence among these cells, as well as to generate ectopic HCG fates in combination with LIN-12 or EGF signaling. While increased Wnt signaling induces predominantly 1 degrees HCG fates, increased LIN-12 or EGF signaling in combination with MAB-5 overexpression promotes 2 degrees HCG fates in anterior Pn.p cells, suggesting distinctive functions of Wnt, LIN-12, and EGF signaling in specification of HCG fates. Lastly, wild-type mab-5 function is necessary for normal P(9-11).p fate specification, indicating that regulation of ectopic HCG fate formation revealed in anterior Pn.p cells reflect mechanisms of pattern formation during normal hook development.

  3. SynMuv genes redundantly inhibit lin-3/EGF expression to prevent inappropriate vulval induction in C. elegans.

    Science.gov (United States)

    Cui, Mingxue; Chen, Jun; Myers, Toshia R; Hwang, Byung Joon; Sternberg, Paul W; Greenwald, Iva; Han, Min

    2006-05-01

    Activation of EGFR-Ras-MAPK signaling in vulval precursor cells (VPCs) by LIN-3/EGF from the gonad induces vulval development in C. elegans. The prevailing view is that LIN-3 overcomes an "inhibitory signal" from the adjacent hyp7 hypodermal syncytium. This view originated from observations indicating that inactivation of functionally redundant Synthetic Multivulva (SynMuv) genes in hyp7 can activate EGFR-Ras-MAPK signaling in the VPCs. Many SynMuv genes encode transcription and chromatin-associated factors, including the Rb ortholog. Here, we show that the SynMuv A and SynMuv B gene classes are functionally redundant for transcriptional repression of the key target gene, lin-3/EGF, in the hypodermis. These observations necessitate a revision of the concept of "inhibitory signaling." They also underscore the importance of preventing inappropriate cell signaling during development and suggest that derepression of growth factors may be the mechanism by which tumor suppressor genes such as Rb can have cell nonautonomous effects.

  4. LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML.

    Science.gov (United States)

    Zhou, Jianbiao; Chan, Zit-Liang; Bi, Chonglei; Lu, Xiao; Chong, Phyllis S Y; Chooi, Jing-Yuan; Cheong, Lip-Lee; Liu, Shaw-Cheng; Ching, Ying Qing; Zhou, Yafeng; Osato, Motomi; Tan, Tuan Zea; Ng, Chin Hin; Ng, Siok-Bian; Wang, Shi; Zeng, Qi; Chng, Wee-Joo

    2017-03-01

    PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis.Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. ©2016 AACR.

  5. Properties of the fullerene C60-containing PN Lin49 in the SMC; Explanations of strong near-IR excess

    Science.gov (United States)

    Otsuka, Masaaki; Kemper, Francisca; Leal-Ferreira, Marcelo L.; Aleman, Isabel; Bernard-Salas, Jeronimo; Cami, Jan; Ochsendorf, Bram; Peeters, Els

    2016-07-01

    We performed a detailed spectroscopic analysis of the fullerene C6o-containing planetary nebula (PN) Lin49 in the Small Magellanic Cloud (SMC). Lin49 is a C-rich and metal- deficient PN (Z∼⃒0.0006) and its nebular abundances are in agreement with the AGB model for the initially 1.25Mʘ stars with the metallicity Z = 0.001 of Fishlock et al. (2014, [1]). By stellar absorption fitting with TLUSTY, we derived stellar abundances, effective temperature, and surface gravity. We constructed the photo-ionization model with CLOUDY in order to investigate physical conditions of Lin49. The model with the 0.005-0.1 μm radius graphite and a constant hydrogen density shell could not fit the ∼⃒1-5 μm SED owing to the strong near-IR excess. We propose that the near-IR excess indicates (1) the presence of extremely small carbon molecules or (2) the presence of high-density structure surrounding the central star.

  6. Human Lin28 Forms a High-Affinity 1:1 Complex with the 106~363 Cluster miRNA miR-363.

    Science.gov (United States)

    Peters, Daniel T; Fung, Herman K H; Levdikov, Vladimir M; Irmscher, Tobias; Warrander, Fiona C; Greive, Sandra J; Kovalevskiy, Oleg; Isaacs, Harry V; Coles, Mark; Antson, Alfred A

    2016-09-13

    Lin28A is a post-transcriptional regulator of gene expression that interacts with and negatively regulates the biogenesis of let-7 family miRNAs. Recent data suggested that Lin28A also binds the putative tumor suppressor miR-363, a member of the 106~363 cluster of miRNAs. Affinity for this miRNA and the stoichiometry of the protein-RNA complex are unknown. Characterization of human Lin28's interaction with RNA has been complicated by difficulties in producing stable RNA-free protein. We have engineered a maltose binding protein fusion with Lin28, which binds let-7 miRNA with a Kd of 54.1 ± 4.2 nM, in agreement with previous data on a murine homologue. We show that human Lin28A binds miR-363 with a 1:1 stoichiometry and with a similar, if not higher, affinity (Kd = 16.6 ± 1.9 nM). Further analysis suggests that the interaction of the N-terminal cold shock domain of Lin28A with RNA is salt-dependent, supporting a model in which the cold shock domain allows the protein to sample RNA substrates through transient electrostatic interactions.

  7. Intraocular Medulloepitheliomas and Embryonal Tumors With Multilayered Rosettes of the Brain: Comparative Roles of LIN28A and C19MC.

    Science.gov (United States)

    Jakobiec, Frederick A; Kool, Marcel; Stagner, Anna M; Pfister, Stefan M; Eagle, Ralph C; Proia, Alan D; Korshunov, Andrey

    2015-06-01

    To compare immunohistochemical and genetic overlaps and differences between intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain. Retrospective histopathologic, immunohistochemical, and genetic analysis of 20 intraocular medulloepitheliomas. (1) Review of clinical data and hematoxylin-eosin-stained sections with (2) immunohistochemical staining of paraffin sections using a polyclonal antibody against the protein LIN28A, and (3) fluorescence in situ hybridization (FISH) testing for the amplification of the genetic locus 19q13.42 involving the C19MC cluster of miRNA. Ten retinoblastomas served as controls and to determine the specificity of these biomarkers for intraocular medulloepitheliomas. Nineteen of the 20 intraocular medulloepitheliomas were either diffusely or focally LIN28A positive (weak, moderate, or strong). The most intense positivity correlated with aggressive behavior such as intraocular tissue invasion or extraocular extension. None of the cases studied by FISH harbored an amplicon for C19MC. The 10 retinoblastomas were LIN28A and C19MC negative. LIN28A has a putative role in oncogenesis and is found only in embryonic cells and malignancies. Intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain both display LIN28A positivity. Only the latter, however, display amplification of the 19q13.42 locus involving C19MC, implying that other causative factors are at play in intraocular medulloepitheliomas. More aggressive tumor behavior within the eye can be partially predicted by LIN28A staining intensity. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7).

    Science.gov (United States)

    Thornton, James E; Chang, Hao-Ming; Piskounova, Elena; Gregory, Richard I

    2012-10-01

    The pluripotency factor Lin28 recruits a 3' terminal uridylyl transferase (TUTase) to selectively block let-7 microRNA biogenesis in undifferentiated cells. Zcchc11 (TUTase4/TUT4) was previously identified as an enzyme responsible for Lin28-mediated pre-let-7 uridylation and control of let-7 expression. Here we investigate the protein and RNA determinants for this interaction. Biochemical dissection and reconstitution assays reveal the TUTase domains necessary and sufficient for Lin28-enhanced pre-let-7 uridylation. A single C2H2-type zinc finger domain of Zcchc11 was found to be responsible for the functional interaction with Lin28. We identify Zcchc6 (TUTase7) as an alternative TUTase that functions with Lin28 in vitro, and accordingly, we find Zcchc11 and Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells. Our study indicates that Lin28 uses two different TUTases to control let-7 expression and has important implications for stem cell biology as well as cancer.

  9. Importance of the NCp7-like domain in the recognition of pre-let-7g by the pluripotency factor Lin28.

    Science.gov (United States)

    Desjardins, Alexandre; Yang, Ao; Bouvette, Jonathan; Omichinski, James G; Legault, Pascale

    2012-02-01

    The pluripotency factor Lin28 is a highly conserved protein comprising a unique combination of RNA-binding motifs, an N-terminal cold-shock domain and a C-terminal region containing two retroviral-type CCHC zinc-binding domains. An important function of Lin28 is to inhibit the biogenesis of the let-7 family of microRNAs through a direct interaction with let-7 precursors. Here, we systematically characterize the determinants of the interaction between Lin28 and pre-let-7 g by investigating the effect of protein and RNA mutations on in vitro binding. We determine that Lin28 binds with high affinity to the extended loop of pre-let-7 g and that its C-terminal domain contributes predominantly to the affinity of this interaction. We uncover remarkable similarities between this C-terminal domain and the NCp7 protein of HIV-1, not only in terms of primary structure but also in their modes of RNA binding. This NCp7-like domain of Lin28 recognizes a G-rich bulge within pre-let-7 g, which is adjacent to one of the Dicer cleavage sites. We hypothesize that the NCp7-like domain initiates RNA binding and partially unfolds the RNA. This partial unfolding would then enable multiple copies of Lin28 to bind the extended loop of pre-let-7 g and protect the RNA from cleavage by the pre-microRNA processing enzyme Dicer.

  10. Double negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells

    Science.gov (United States)

    Yang, Xiaojun; Lin, Xiaojuan; Zhong, Xiaomin; Kaur, Sippy; Li, Ning; Liang, Shun; Lassus, Heini; Wang, Liping; Katsaros, Dionyssios; Montone, Kathleen; Zhao, Xia; Zhang, Youcheng; Bützow, Ralf; Coukos, George; Zhang, Lin

    2010-01-01

    A relatively rare aldehyde dehydrogenase 1 (ALDH1) positive “stem cell-like” subpopulation of tumor cells has the unique ability to initiate and perpetuate tumor growth; moreover it is highly resistant to chemotherapy and significantly associated with poor clinical outcomes. The development of more effective therapies for cancer requires targeting of this cell population. Using cDNA microarray analysis, we identified that the expression of the C. elegans lin-28 homolog (LIN28) was positively correlated with the percentage of ALDH1+ tumor cells; this was further validated in an independent set of tissue arrays (n=197). Both lose-of-function and gain-of-function studies demonstrated that LIN28 plays a critical role in the maintenance of ALDH1+ tumor cells. In addition, we found that there is a double negative feedback loop between LIN28 and let-7 in tumor cells, and that let-7 negatively regulates ALDH1+ tumor cells. Finally, we report that a LIN28/let-7 loop modulates self renewal and differentiation of mammary gland epithelial progenitor cells. Our data provide evidence that cancer stem cells may arise through a “reprogramming-like” mechanism. A rebalancing of the LIN28/let-7 regulatory loop could be a novel therapeutic strategy to target ALDH1+ cancer stem cells. PMID:21045151

  11. Human Lin28 Forms a High-Affinity 1:1 Complex with the 106~363 Cluster miRNA miR-363

    Science.gov (United States)

    2016-01-01

    Lin28A is a post-transcriptional regulator of gene expression that interacts with and negatively regulates the biogenesis of let-7 family miRNAs. Recent data suggested that Lin28A also binds the putative tumor suppressor miR-363, a member of the 106~363 cluster of miRNAs. Affinity for this miRNA and the stoichiometry of the protein–RNA complex are unknown. Characterization of human Lin28’s interaction with RNA has been complicated by difficulties in producing stable RNA-free protein. We have engineered a maltose binding protein fusion with Lin28, which binds let-7 miRNA with a Kd of 54.1 ± 4.2 nM, in agreement with previous data on a murine homologue. We show that human Lin28A binds miR-363 with a 1:1 stoichiometry and with a similar, if not higher, affinity (Kd = 16.6 ± 1.9 nM). Further analysis suggests that the interaction of the N-terminal cold shock domain of Lin28A with RNA is salt-dependent, supporting a model in which the cold shock domain allows the protein to sample RNA substrates through transient electrostatic interactions. PMID:27559824

  12. Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB).

    Science.gov (United States)

    Chi, Woo; Reinke, Valerie

    2006-08-01

    In Caenorhabditis elegans, EFL-1 (E2F), DPL-1 (DP) and LIN-35 (pRb) act coordinately in somatic tissues to inhibit ectopic cell division, probably by repressing the expression of target genes. EFL-1, DPL-1 and LIN-35 are also present in the germline, but do not always act together. Strong loss-of-function mutations in either efl-1 or dpl-1 cause defects in oogenesis that result in sterility, while lin-35 mutants are fertile with reduced broods. Microarray-based expression profiling of dissected gonads from efl-1, dpl-1 and lin-35 mutants reveals that EFL-1 and DPL-1 promote expression of an extensively overlapping set of target genes, consistent with the expectation that these two proteins function as a heterodimer. Regulatory regions upstream of many of these target genes have a canonical E2F-binding site, suggesting that their regulation by EFL-1/DPL-1 is direct. Many EFL-1/DPL-1 responsive genes encode proteins required for oogenesis and early embryogenesis, rather than cell cycle components. By contrast, LIN-35 appears to function primarily as a repressor of gene expression in the germline, and the genes that it acts on are for the most part distinct from those regulated by EFL-1 and/or DPL-1. Thus, in vivo, C. elegans E2F directly promotes oogenesis and embryogenesis through the activation of a tissue-specific transcriptional program that does not require LIN-35.

  13. Characteristics of Aerosol Ionic Compositions in Summer 2003 at Lin'an of Yangtze Delta Region

    Institute of Scientific and Technical Information of China (English)

    YAN Peng; ZHANG Yangmei; YANG Dongzhen; TANG Jie; ZHOU Xiuji

    2006-01-01

    With the size-resolved aerosol mass and ion composition data obtained at Lin'an regional atmospheric pollution monitoring station in July 2003, the size distributions of aerosol mass and ionic components, and the correlations between major ion pairs were analyzed. The primary results indicate that in the period of in-situ measurement, the aerosols are mainly composed of fine particles. The mass of aerosols with size less than 2.1 μm accounts for 66% of the total mass of all size ranges, in which about 50% of the mass is contributed by the particles with size less than 0.65 μm. Similar to the size distributions of aerosol mass,the water-soluble ions are mainly concentrated in the size range of <0.65μm, accounting for about 77% of the sum of analyzed ions, and the ions within the range of <2.1 μm reach 88%. The sulfate, ammonium,and potassium are the dominant ionic components in fine particles (particle size less than 2.1 μm). Ion correlation analysis suggests that the sulfates in fine particles are mostly in the compounds of (NH4)2SO4,Na2SO4, and K2SO4, but for submicron particles the sulfates are mainly in the form of (NH4)2SO4.

  14. OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development.

    Directory of Open Access Journals (Sweden)

    Hidetoshi Komatsu

    2008-08-01

    Full Text Available Notch signaling is critical for cell fate decisions during development. Caenorhabditis elegans and vertebrate Notch ligands are more diverse than classical Drosophila Notch ligands, suggesting possible functional complexities. Here, we describe a developmental role in Notch signaling for OSM-11, which has been previously implicated in defecation and osmotic resistance in C. elegans. We find that complete loss of OSM-11 causes defects in vulval precursor cell (VPC fate specification during vulval development consistent with decreased Notch signaling. OSM-11 is a secreted, diffusible protein that, like previously described C. elegans Delta, Serrate, and LAG-2 (DSL ligands, can interact with the lineage defective-12 (LIN-12 Notch receptor extracellular domain. Additionally, OSM-11 and similar C. elegans proteins share a common motif with Notch ligands from other species in a sequence defined here as the Delta and OSM-11 (DOS motif. osm-11 loss-of-function defects in vulval development are exacerbated by loss of other DOS-motif genes or by loss of the Notch ligand DSL-1, suggesting that DOS-motif and DSL proteins act together to activate Notch signaling in vivo. The mammalian DOS-motif protein Deltalike1 (DLK1 can substitute for OSM-11 in C. elegans development, suggesting that DOS-motif function is conserved across species. We hypothesize that C. elegans OSM-11 and homologous proteins act as coactivators for Notch receptors, allowing precise regulation of Notch receptor signaling in developmental programs in both vertebrates and invertebrates.

  15. Chinese Economy to Continue to Grow Despite Pitfalls:Economists

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    The Chinese economy will continue to maintain a rapid growth rate for a considerable period of time to come. predicted leading Chinese economists. These economists include Justin Lin, Zhang Weiying, YiGang, Zhou Qiren and Fan Gang.

  16. DPL-1 DP, LIN-35 Rb and EFL-1 E2F act with the MCD-1 zinc-finger protein to promote programmed cell death in Caenorhabditis elegans.

    Science.gov (United States)

    Reddien, Peter W; Andersen, Erik C; Huang, Michael C; Horvitz, H Robert

    2007-04-01

    The genes egl-1, ced-9, ced-4, and ced-3 play major roles in programmed cell death in Caenorhabditis elegans. To identify genes that have more subtle activities, we sought mutations that confer strong cell-death defects in a genetically sensitized mutant background. Specifically, we screened for mutations that enhance the cell-death defects caused by a partial loss-of-function allele of the ced-3 caspase gene. We identified mutations in two genes not previously known to affect cell death, dpl-1 and mcd-1 (modifier of cell death). dpl-1 encodes the C. elegans homolog of DP, the human E2F-heterodimerization partner. By testing genes known to interact with dpl-1, we identified roles in cell death for four additional genes: efl-1 E2F, lin-35 Rb, lin-37 Mip40, and lin-52 dLin52. mcd-1 encodes a novel protein that contains one zinc finger and that is synthetically required with lin-35 Rb for animal viability. dpl-1 and mcd-1 act with efl-1 E2F and lin-35 Rb to promote programmed cell death and do so by regulating the killing process rather than by affecting the decision between survival and death. We propose that the DPL-1 DP, MCD-1 zinc finger, EFL-1 E2F, LIN-35 Rb, LIN-37 Mip40, and LIN-52 dLin52 proteins act together in transcriptional regulation to promote programmed cell death.

  17. Variation Characteristics of Ambient NMHCs at Shangdianzi and Lin'an Regional GAW Sites

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In order to study the variation characteristics of concentration of the atmospheric non-methane hydrocarbons (NMHCs) in background area of China, the atmospheric concentrations of NMHCs were measured at Lin'an (LA) regional GAW (Global Atmosphere Watch) Station (30°25'N, 119°44'E; 132.0 m ASL) and Shangdianzi (SDZ) regional GAW Station (40°19'N, 117°07'E; 286.5 m ASL) with the sorbent sorp-tion/thermal desorption/gas chromatographic method. Totally 145 samples were collected during the period of October 2003 and July 2004. Among the 52 NMHC species of C2-C10 detected there were 26 alkanes, 17 alkenes, and 9 aromatics. The average concentrations of total NMHCs (TNMHCs) at LA and SDZ were (238.5±126.0)×KT9C and (278.7±185.5)x10-9C, respectively. The results showed the ambient concentrations of TNMHCs at LA regional GAW Station increased notably over the last decade. The compositions of NMHCs at SDZ and LA were relatively similar. The proportions of alkanes, alkenes, and aromatics for SDZ and LA were hi ranges of (27.3±4.0)%, (10.3±3.5)%, and (62.5±4.8)%, respectively, with features of vehicle exhaust emissions. The concentrations of NMHCs at the two sites showed obvious diurnal and seasonal variations. The TNMHC concentrations in October-November were high at the two sites, and relatively low in April and July. The diurnal variation patterns at the sites were different. The high TNMHC concentrations at SDZ normally appeared in evening and night, but appeared in morning at LA. The TNMHCs concentrations at the two sites were significantly influenced by the meteorological condition. The high TNMHC concentration associated with the local wind from the urban areas or traffic in upper reaches.

  18. Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia.

    Science.gov (United States)

    De Luca, Luciana; Trino, Stefania; Laurenzana, Ilaria; Tagliaferri, Daniela; Falco, Geppino; Grieco, Vitina; Bianchino, Gabriella; Nozza, Filomena; Campia, Valentina; D'Alessio, Francesca; La Rocca, Francesco; Caivano, Antonella; Villani, Oreste; Cilloni, Daniela; Musto, Pellegrino; Del Vecchio, Luigi

    2017-06-01

    Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1-mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in 'AML with maturation' (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition.

  19. Contribución al conocimiento de la Epizootiología y Biología del Cathartes aura Lin (Contribution to the knowledge of the Epizootiology and Biology of the Cathartes aura Lin.)

    OpenAIRE

    Isacc J. Rotella; Enrique A. Silveira,; Lázaro Delgado; Maria J. Manso; Juana R. Perdomo; Reinaldo Campos

    2006-01-01

    Con el objetivo de esclarecer el papel epizoodémico del Catharthes aura Lin. (aura) y el fundamento de su resistencia frente a los microorganismos y toxinas que ingiere, se realizó una investigación en 53 ejemplares, que comprendió la infección artificial de 12 animales con B. abortus, M. bovis, S. aureus y S. typhimurium y, en animales no inoculados, bacteriología, parasitología, serología (brucelosis y leptospirosis), electroforesis del suero, hematología y medición del pH de órganos del tr...

  20. The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans.

    Science.gov (United States)

    Pu, Pu; Stone, Craig E; Burdick, Joshua T; Murray, John I; Sundaram, Meera V

    2016-12-30

    Lipocalins are secreted cup-shaped glycoproteins that bind sterols, fatty acids, and other lipophilic molecules. Lipocalins have been implicated in a wide array of processes related to lipophilic cargo transport, sequestration and signaling, and several are used as biomarkers for human disease, but the functions of most lipocalins remain poorly understood. Here we show that the C. elegans lipocalin LPR-1 is required to maintain apical membrane integrity and a continuous lumen in two narrow, unicellular tubes, the excretory duct and pore, during a period of rapid lumen elongation. LPR-1 fusion protein is expressed by the duct and pore and accumulates both intracellularly and in apical extracellular compartments, but it can also function cell non-autonomously when provided from outside of the excretory system. lpr-1 mutant defects can be rescued by increased signaling through the Epidermal growth factor (EGF) - Ras - Extracellular signal regulated kinase (ERK) pathway, which promotes the more elongated duct vs. less elongated pore tube fate. Spatial and temporal rescue experiments indicate that Ras signaling acts within the duct and pore tubes during or prior to cell fate determination to bypass the requirement for LPR-1. lpr-1 mutations did not disrupt LIN-3/EGF-dependent duct fate specification, prevent functioning of any specific LIN-3/EGF isoform, or alter LET-23/EGFR localization, and reduced signaling did not phenocopy or enhance lpr-1 mutant defects. These data suggest that LPR-1 protects lumen integrity through a LIN-3/EGF-independent mechanism, but that increased signaling upregulates some target(s) that can compensate for lpr-1 absence.

  1. Optical and electrical properties of zinc oxide thin films with low resistivity via Li-N dual-acceptor doping

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Daoli, E-mail: zhang_daoli@mail.hust.edu.cn [Department of Electronic Science and Technology, Huazhong University of Science and Technology, No. 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Wuhan National Laboratory for Optoelectronics, 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Zhang Jianbing [Department of Electronic Science and Technology, Huazhong University of Science and Technology, No. 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Wuhan National Laboratory for Optoelectronics, 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Guo Zhe [Department of Electronic Science and Technology, Huazhong University of Science and Technology, No. 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Miao Xiangshui [Department of Electronic Science and Technology, Huazhong University of Science and Technology, No. 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China); Wuhan National Laboratory for Optoelectronics, 1037 Luoyu Road, Hongshan District, Wuhan City, Hubei Province 430074 (China)

    2011-05-19

    Highlights: > Zinc oxide films have been deposited on glass substrates by Li-N dual-acceptor doping method via a modified SILAR method. > The resistivity of ZnO film was found to be 1.04 {Omega} cm with a Hall mobility of 0.749 cm{sup 2} V{sup -1} s{sup -1}, carrier concentration of 8.02 x 1018 cm{sup -3}, and transmittance of about 80% in visible range showing good crystallinity with prior c-axis orientation. > A shallow acceptor level of 91 meV is identified from free-to-neutral-acceptor transitions. > Another deep level of 255 meV was ascribed to Li{sub Zn}-Li{sub i} complex. - Abstract: Zinc oxide thin films with low resistivity have been deposited on glass substrates by Li-N dual-acceptor doping method via a modified successive ionic layer adsorption and reaction process. The thin films were systematically characterized via scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction, ultraviolet-visible spectrophotometry and fluorescence spectrophotometry. The resistivity of zinc oxide film was found to be 1.04 {Omega} cm with a Hall mobility of 0.749 cm{sup 2} V{sup -1} s{sup -1} and carrier concentration of 8.02 x 10{sup 18} cm{sup -3}. The Li-N dual-acceptor doped zinc oxide films showed good crystallinity with prior c-axis orientation, and high transmittance of about 80% in visible range. Moreover, the effects of Li doping level and other parameters on crystallinity, electrical and ultraviolet emission of zinc oxide films were investigated.

  2. Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, S.; Tanaka, J.; Okada, S.; Isobe, T.; Yamamoto, G.; Yasuhara, R.; Irie, T.; Akiyama, C.; Kohno, Y.; Tachikawa, T.; Mishima, K., E-mail: mishima-k@dent.showa-u.ac.jp

    2013-05-01

    Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment - Highlights: ► Lin28a is a SP cell-specific factor in oral squamous cell carcinoma (OSCC) cells. ► SP cells in OSCC cells show cancer stem cell-like properties. ► Lin28a regulates OSCC proliferative and invasive activities.

  3. Discovery of a Small-Molecule Inhibitor of Protein-MicroRNA Interaction Using Binding Assay with a Site-Specifically Labeled Lin28.

    Science.gov (United States)

    Lim, Donghyun; Byun, Wan Gi; Koo, Ja Young; Park, Hankum; Park, Seung Bum

    2016-10-07

    MicroRNAs (miRNAs) regulate gene expression by targeting protein-coding transcripts that are involved in various cellular processes. Thus, miRNA biogenesis has been recognized as a novel therapeutic target. Especially, the let-7 miRNA family is well-known for its tumor suppressor functions and is downregulated in many cancer cells. Lin28 protein binds to let-7 miRNA precursors to inhibit their maturation. Herein, we developed a FRET-based, high-throughput screening system to identify small-molecule inhibitors of the Lin28-let-7 interaction. We employed unnatural amino acid mutagenesis and bioorthogonal chemistry for the site-specific fluorescent labeling of Lin28, which ensures the robustness and reliability of the FRET-based protein-miRNA binding assay. Using this direct binding assay, we identified an inhibitor of the oncogenic Lin28-let-7 interaction. The inhibitor enhanced the production of let-7 miRNAs in Lin28-expressing cancer cells and reduced the level of let-7 target oncogene products.

  4. Short loop-targeting oligoribonucleotides antagonize Lin28 and enable pre-let-7 processing and suppression of cell growth in let-7-deficient cancer cells.

    Science.gov (United States)

    Roos, Martina; Rebhan, Mario A E; Lucic, Matije; Pavlicek, David; Pradere, Ugo; Towbin, Harry; Civenni, Gianluca; Catapano, Carlo V; Hall, Jonathan

    2015-01-01

    MicroRNAs (miRNAs) originate from stem-loop-containing precursors (pre-miRNAs, pri-miRNAs) and mature by means of the Drosha and Dicer endonucleases and their associated factors. The let-7 miRNAs have prominent roles in developmental differentiation and in regulating cell proliferation. In cancer, the tumor suppressor function of let-7 is abrogated by overexpression of Lin28, one of several RNA-binding proteins that regulate let-7 biogenesis by interacting with conserved motifs in let-7 precursors close to the Dicer cleavage site. Using in vitro assays, we have identified a binding site for short modified oligoribonucleotides ('looptomirs') overlapping that of Lin28 in pre-let-7a-2. These looptomirs selectively antagonize the docking of Lin28, but still permit processing of pre-let-7a-2 by Dicer. Looptomirs restored synthesis of mature let-7 and inhibited growth and clonogenic potential in Lin28 overexpressing hepatocarcinoma cells, thereby demonstrating a promising new means to rescue defective miRNA biogenesis in Lin28-dependent cancers. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas.

    Science.gov (United States)

    Yao, Kai; Qiu, Suo; Tian, Lin; Snider, William D; Flannery, John G; Schaffer, David V; Chen, Bo

    2016-09-27

    In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs) readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retinas activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription. Deletion of Lin28 abolishes β-catenin-mediated effects on MG proliferation, and Lin28 gene transfer stimulates MG proliferation. We further demonstrate that let-7 miRNAs are critically involved in Wnt/Lin28-regulated MG proliferation. Intriguingly, a subset of cell-cycle-reactivated MGs express markers for amacrine cells. Together, these results reveal a key role of Wnt-Lin28-let7 miRNA signaling in regulating proliferation and neurogenic potential of MGs in the adult mammalian retina. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas

    Directory of Open Access Journals (Sweden)

    Kai Yao

    2016-09-01

    Full Text Available In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retinas activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription. Deletion of Lin28 abolishes β-catenin-mediated effects on MG proliferation, and Lin28 gene transfer stimulates MG proliferation. We further demonstrate that let-7 miRNAs are critically involved in Wnt/Lin28-regulated MG proliferation. Intriguingly, a subset of cell-cycle-reactivated MGs express markers for amacrine cells. Together, these results reveal a key role of Wnt-Lin28-let7 miRNA signaling in regulating proliferation and neurogenic potential of MGs in the adult mammalian retina.

  7. On HE Lin's Thought of Unity between Knowledge and Action%论贺麟的知行合一

    Institute of Scientific and Technical Information of China (English)

    张建华

    2012-01-01

    The essence of HE Lin's view of unity between knowledge and action is the double structure. And he stressed the content of learning. And his view that knowledge precedes action is the necessary conclusion of his new theory of mind.%贺麟的知行合一论其实质是两层结构,贺麟重点发挥了知行合一的学理内容,而其知主行从的观点则是“新心学”体系的必然结论。

  8. Realization of stable p-type ZnO thin films using Li-N dual acceptors

    Energy Technology Data Exchange (ETDEWEB)

    Rao, T. Prasada, E-mail: prasadview@gmail.com [Advanced Materials Laboratory, Department of Physics, National Institute of Technology, Tiruchirappalli- 620 015 (India); Kumar, M.C. Santhosh, E-mail: santhoshmc@nitt.edu [Advanced Materials Laboratory, Department of Physics, National Institute of Technology, Tiruchirappalli- 620 015 (India)

    2011-09-01

    Highlights: > We have presented a promising Li-N dual acceptor doping method to realize p-type ZnO films via spray pyrolysis. > The influence of concentration of Li-N on the structural, electrical, and optical properties of p-type ZnO:(Li, N) films were investigated in detail. > It is found that (Li, N):ZnO films deposited on glass substrate show the preferential orientation of (002) plane. > The Hall Effect measurements exhibited p-type behaviour on (Li, N):ZnO thin films and the stability of the samples were verified by aging studies. - Abstract: Lithium and nitrogen dual acceptors-doped p-type ZnO thin films have been prepared using spray pyrolysis technique. The influence of dual acceptor (Li, N) doping on the structural, electrical, and optical properties of (Li, N):ZnO films are investigated in detail. The (Li, N):ZnO films exhibit good crystallinity with a preferred c-axis orientation. From AFM studies, it is found that the surface roughness of the thin films increases with the increase of doping percentage. The Hall Effect measurements showed p-type conductivity. The Hall measurements have been performed periodically up to seven months and it is observed that the films show p-type conductivity throughout the period of observation. The samples with Li:N ratio of 8:8 mol% showed the lowest resistivity of 35.78 {Omega} cm, while sample with Li:N ratio of 6:6 mol% showed highest carrier concentration. The PL spectra of (Li, N):ZnO films show a strong UV emission at room temperature. Furthermore, PL spectra show low intensity in deep level transition, indicating a low density of native defects. This indicates that the formation of intrinsic defects is effectively suppressed by dual acceptor (Li, N) doping in ZnO thin films. The chemical bonding states of N and Li in the films were examined by XPS analysis.

  9. Relevance of the Lin's and Host hydropedological models to predict grape yield and wine quality

    Science.gov (United States)

    Costantini, E. A. C.; Pellegrini, S.; Bucelli, P.; Storchi, P.; Vignozzi, N.; Barbetti, R.; Campagnolo, S.

    2009-09-01

    The adoption of precision agriculture in viticulture could be greatly enhanced by the diffusion of straightforward and easy to be applied hydropedological models, able to predict the spatial variability of available soil water. The Lin's and Host hydropedological models were applied to standard soil series descriptions and hillslope position, to predict the distribution of hydrological functional units in two vineyard and their relevance for grape yield and wine quality. A three-years trial was carried out in Chianti (Central Italy) on Sangiovese. The soils of the vineyards differentiated in structure, porosity and related hydropedological characteristics, as well as in salinity. Soil spatial variability was deeply affected by earth movement carried out before vine plantation. Six plots were selected in the different hydrological functional units of the two vineyards, that is, at summit, backslope and footslope morphological positions, to monitor soil hydrology, grape production and wine quality. Plot selection was based upon a cluster analysis of local slope, topographic wetness index (TWI), and cumulative moisture up to the root limiting layer, appreciated by means of a detailed combined geophysical survey. Water content, redox processes and temperature were monitored, as well as yield, phenological phases, and chemical analysis of grapes. The isotopic ratio δ13C was measured in the wine ethanol upon harvesting to evaluate the degree of stress suffered by vines. The grapes in each plot were collected for wine making in small barrels. The wines obtained were analysed and submitted to a blind organoleptic testing. The results demonstrated that the combined application of the two hydropedological models can be used for the prevision of the moisture status of soils cultivated with grape during summertime in Mediterranean climate. As correctly foreseen by the models, the amount of mean daily transpirable soil water (TSW) during the growing season differed

  10. Relevance of the Lin's and Host hydropedological models to predict grape yield and wine quality

    Directory of Open Access Journals (Sweden)

    E. A. C. Costantini

    2009-09-01

    Full Text Available The adoption of precision agriculture in viticulture could be greatly enhanced by the diffusion of straightforward and easy to be applied hydropedological models, able to predict the spatial variability of available soil water. The Lin's and Host hydropedological models were applied to standard soil series descriptions and hillslope position, to predict the distribution of hydrological functional units in two vineyard and their relevance for grape yield and wine quality. A three-years trial was carried out in Chianti (Central Italy on Sangiovese. The soils of the vineyards differentiated in structure, porosity and related hydropedological characteristics, as well as in salinity. Soil spatial variability was deeply affected by earth movement carried out before vine plantation. Six plots were selected in the different hydrological functional units of the two vineyards, that is, at summit, backslope and footslope morphological positions, to monitor soil hydrology, grape production and wine quality. Plot selection was based upon a cluster analysis of local slope, topographic wetness index (TWI, and cumulative moisture up to the root limiting layer, appreciated by means of a detailed combined geophysical survey. Water content, redox processes and temperature were monitored, as well as yield, phenological phases, and chemical analysis of grapes. The isotopic ratio δ13C was measured in the wine ethanol upon harvesting to evaluate the degree of stress suffered by vines. The grapes in each plot were collected for wine making in small barrels. The wines obtained were analysed and submitted to a blind organoleptic testing.

    The results demonstrated that the combined application of the two hydropedological models can be used for the prevision of the moisture status of soils cultivated with grape during summertime in Mediterranean climate. As correctly foreseen by the models, the amount of mean daily transpirable soil water (TSW during

  11. Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.

    Science.gov (United States)

    Wen, Juyi; Liu, Hongliang; Wang, Qiming; Liu, Zhensheng; Li, Yangkai; Xiong, Huihua; Xu, Ting; Li, Peng; Wang, Li-E; Gomez, Daniel R; Mohan, Radhe; Komaki, Ritsuko; Liao, Zhongxing; Wei, Qingyi

    2014-07-01

    LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumourigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A) and LIN28B (rs314280 G>A, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio(chemo)therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders. Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ⩾3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR=2.97 and 2.23, 95% confidence interval (CI)=1.32-6.72 and 1.01-4.94, P=0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR=2.30 and 2.00, 95% CI=1.24-4.28 and 1.11-3.62, and P=0.008 and 0.022, respectively). Further stratified analyses showed a more consistent and profound risk in the subgroups of age LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings. Copyright © 2014. Published by Elsevier Ltd.

  12. Role of XIST/miR-29a/LIN28A pathway in denatured dermis and human skin fibroblasts (HSFs) after thermal injury.

    Science.gov (United States)

    Guo, Le; Huang, Xu; Liang, Pengfei; Zhang, Pihong; Zhang, Minghua; Ren, Licheng; Zeng, Jizhang; Cui, Xv; Huang, Xiaoyuan

    2017-08-03

    Denatured dermis is a part of the dermis in deep burn wound and has the ability to restore normal morphology and function. In our previous study, we revealed that miR-29a downregulation in denatured dermis may help burn wound healing in the later phase, and further enhance type I collagen synthesis. LIN28A, a highly-conserved RNA binding protein expressed during embryogenesis, plays roles in development, pluripotency, metabolism, as well as tissue repair in adults. In the present study, we investigated the functional roles of LIN28A in human skin fibroblasts (HSFs) and extracellular matrix (ECM), and the interaction between miR-29a and LIN28A. In recent years, long non-coding RNAs have been reported to play a key role in normal development and physiology, as well as in disease development. By using online tools, we screened out several candidate lncRNAs of miR-29a, among which XIST was inversely regulated by miR-29a. XIST, one of the first found cancer-associated lncRNAs, has been frequently reported to play major role in several biological processes. Further, we evaluated the roles and mechanism of XIST in HSF proliferation, migration, and ECM synthesis. Through regulation of miR-29a/LIN28A, XIST knockdown suppressed HSF proliferation, migration, and ECM synthesis. In denatured dermis tissues, XIST, and LIN28A expression was upregulated, miR-29a expression was downregulated. Taken together, promoting XIST expression in denatured dermis, thus to inhibit miR-29a and promote LIN28A expression, further promote HSF proliferation, migration, and ECM synthesis presents a promising strategy for denatured dermis repair. © 2017 Wiley Periodicals, Inc.

  13. A novel C19MC amplified cell line links Lin28/let-7 to mTOR signaling in embryonal tumor with multilayered rosettes.

    Science.gov (United States)

    Spence, Tara; Perotti, Christian; Sin-Chan, Patrick; Picard, Daniel; Wu, Wei; Singh, Anjali; Anderson, Colleen; Blough, Michael D; Cairncross, J Gregory; Lafay-Cousin, Lucie; Strother, Douglas; Hawkins, Cynthia; Narendran, Aru; Huang, Annie; Chan, Jennifer A

    2014-01-01

    Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems. We have established a first cell line, BT183, from a case of ETMR and characterized its molecular and cellular features. LIN28 knockdown was performed in BT183 to examine the potential role of Lin28 in regulating signaling pathway gene expression in ETMR. Cell line findings were corroborated with immunohistochemical studies in ETMR tissues. A drug screen of 73 compounds was performed to identify potential therapeutic targets. The BT183 line maintains C19MC amplification, expresses C19MC-encoded microRNAs, and is tumor initiating. ETMRs, including BT183, have high LIN28 expression and low let-7 miRNA expression, and show evidence of mTOR pathway activation. LIN28 knockdown increases let-7 expression and decreases expression of IGF/PI3K/mTOR pathway components. Pharmacologic inhibition of the mTOR pathway reduces BT183 cell viability. BT183 retains key genetic and histologic features of ETMR. In ETMR, Lin28 is not only a diagnostic marker but also a regulator of genes involved in growth and metabolism. Our findings indicate that inhibitors of the IGF/PI3K/mTOR pathway may be promising novel therapies for these fatal embryonal tumors. As the first patient-derived cell line of these rare tumors, BT183 is an important, unique reagent for investigating ETMR biology and therapeutics.

  14. The Wnt-β-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.

    Science.gov (United States)

    Cai, Wang-Yu; Wei, Tong-Zhen; Luo, Qi-Cong; Wu, Qiu-Wan; Liu, Qing-Feng; Yang, Meng; Ye, Guo-Dong; Wu, Jia-Fa; Chen, Yuan-Yuan; Sun, Guang-Bin; Liu, Yun-Jia; Zhao, Wen-Xiu; Zhang, Zhi-Ming; Li, Bo-An

    2013-07-01

    Wnt signalling through β-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-β-catenin pathway. Expression studies indicated that the Wnt-β-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-β-catenin pathway. Loss of function of Lin28 impairs Wnt-β-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-β-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-β-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-β-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-β-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-β-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.

  15. Generating induced pluripotent stem cells from common marmoset (Callithrix jacchus) fetal liver cells using defined factors, including Lin28.

    Science.gov (United States)

    Tomioka, Ikuo; Maeda, Takuji; Shimada, Hiroko; Kawai, Kenji; Okada, Yohei; Igarashi, Hiroshi; Oiwa, Ryo; Iwasaki, Tsuyoshi; Aoki, Mikio; Kimura, Toru; Shiozawa, Seiji; Shinohara, Haruka; Suemizu, Hiroshi; Sasaki, Erika; Okano, Hideyuki

    2010-09-01

    Although embryonic stem (ES) cell-like induced pluripotent stem (iPS) cells have potential therapeutic applications in humans, they are also useful for creating genetically modified human disease models in nonhuman primates. In this study, we generated common marmoset iPS cells from fetal liver cells via the retrovirus-mediated introduction of six human transcription factors: Oct-3/4, Sox2, Klf4, c-Myc, Nanog, and Lin28. Four to five weeks after introduction, several colonies resembling marmoset ES cells were observed and picked for further expansion in ES cell medium. Eight cell lines were established, and validation analyses of the marmoset iPS cells followed. We detected the expression of ES cell-specific surface markers. Reverse transcription-PCR showed that these iPS cells expressed endogenous Oct-3/4, Sox2, Klf4, c-Myc, Nanog and Lin28 genes, whereas all of the transgenes were silenced. Karyotype analysis showed that two of three iPS cell lines retained a normal karyotype after a 2-month culture. Both embryoid body and teratoma formation showed that marmoset iPS cells had the developmental potential to give rise to differentiated derivatives of all three primary germ layers. In summary, we generated marmoset iPS cells via the transduction of six transcription factors; this provides a powerful preclinical model for studies in regenerative medicine.

  16. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α

    Science.gov (United States)

    Begley, Ulrike; Sosa, Maria Soledad; Avivar-Valderas, Alvaro; Patil, Ashish; Endres, Lauren; Estrada, Yeriel; Chan, Clement TY; Su, Dan; Dedon, Peter C; Aguirre-Ghiso, Julio A; Begley, Thomas

    2013-01-01

    Emerging evidence points to aberrant regulation of translation as a driver of cell transformation in cancer. Given the direct control of translation by tRNA modifications, tRNA modifying enzymes may function as regulators of cancer progression. Here, we show that a tRNA methyltransferase 9-like (hTRM9L/KIAA1456) mRNA is down-regulated in breast, bladder, colorectal, cervix and testicular carcinomas. In the aggressive SW620 and HCT116 colon carcinoma cell lines, hTRM9L is silenced and its re-expression and methyltransferase activity dramatically suppressed tumour growth in vivo. This growth inhibition was linked to decreased proliferation, senescence-like G0/G1-arrest and up-regulation of the RB interacting protein LIN9. Additionally, SW620 cells re-expressing hTRM9L did not respond to hypoxia via HIF1-α-dependent induction of GLUT1. Importantly, hTRM9L-negative tumours were highly sensitive to aminoglycoside antibiotics and this was associated with altered tRNA modification levels compared to antibiotic resistant hTRM9L-expressing SW620 cells. Our study links hTRM9L and tRNA modifications to inhibition of tumour growth via LIN9 and HIF1-α-dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours. PMID:23381944

  17. Production of Acetol by Escherichia coli Lin43 using Glycerol as a Reactant-Improvement of Methylglyoxal Tolerability by Knocking out Gene gloB%大肠杆菌Lin43利用甘油产丙酮醇⎯通过敲除gloB基因改善丙酮醛耐受性

    Institute of Scientific and Technical Information of China (English)

    刘艺; 朱红亮; 胡洪波; 张雪洪

    2014-01-01

    采用重组大肠杆菌 Lin 43利用甘油产丙酮醇。为了改善菌株对丙酮醛的耐受性,采取敲除 glo B基因而不是gloA 基因以阻断丙酮醛的脱毒途径。实验结果表明,菌株 Lin43ΔgloB 对丙酮醛的耐受性要明显优于 Lin43ΔgloA。在含20 g⋅L-1的甘油磷酸盐缓冲液中,通过26 h 静息细胞转化,菌株 Lin43∆gloB pCA24N-yqhE 丙酮醇产量达到2.30 g⋅L-1,并能耐受3.5 mmol⋅L-1的丙酮醛。同时 Lin43∆gloB pCA24N-yqhE 实现重复发酵,第二轮发酵的产量可达1.53 g⋅L-1,丙酮醇的得率与第一轮相同。%Gene gloB instead of gloA in the strain of Escherichia coli Lin43 was knocked out to disrupt the detoxification pathway of methylglyoxal. The results show that the tolerability of strain Lin43ΔgloB is much better than that of the strain Lin43 ΔgloA. After resting the cells of strain Lin43 ΔgloB pCA24N-yqhE in the phosphate buffer with 20 g⋅L-1of glycerol, it produces 2.30 g⋅L-1 of acetol in 26 h and can resist 3.5 mmol⋅L-1 methylglyoxal. Moreover, 1.53 g⋅L-1 acetol can be produced with strain Lin43 ΔgloB pCA24N-yqhE in the second round production, which has similar yield as that of the first round.

  18. C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component

    OpenAIRE

    Howard, Robyn M.; Sundaram, Meera V.

    2002-01-01

    In Caenorhabditis elegans, Ras/ERK and Wnt/β-catenin signaling pathways cooperate to induce P12 and vulval cell fates in a Hox-dependent manner. Here we describe eor-1 and eor-2, two new positively acting nuclear components of the Ras and Wnt pathways. eor-1 and eor-2 act downstream or in parallel to ERK and function redundantly with the Mediator complex gene sur-2 and the functionally related gene lin-25, such that removal of both eor-1/eor-2 and sur-2/lin-25 mimics the removal of a main Ras...

  19. A mechanistic basis for the coordinated regulation of pharyngeal morphogenesis in Caenorhabditis elegans by LIN-35/Rb and UBC-18-ARI-1.

    Directory of Open Access Journals (Sweden)

    Kumaran Mani

    2009-06-01

    Full Text Available Genetic redundancy, whereby two genes carry out seemingly overlapping functions, may in large part be attributable to the intricacy and robustness of genetic networks that control many developmental processes. We have previously described a complex set of genetic interactions underlying foregut development in the nematode Caenorhabditis elegans. Specifically, LIN-35/Rb, a tumor suppressor ortholog, in conjunction with UBC-18-ARI-1, a conserved E2/E3 complex, and PHA-1, a novel protein, coordinately regulates an early step of pharyngeal morphogenesis involving cellular re-orientation. Functional redundancy is indicated by the observation that lin-35; ubc-18 double mutants, as well as certain allelic combinations of pha-1 with either lin-35 or ubc-18, display defects in pharyngeal development, whereas single mutants do not. Using a combination of genetic and molecular analyses, we show that sup-35, a strong recessive suppressor of pha-1-associated lethality, also reverts the synthetic lethality of lin-35; ubc-18, lin-35; pha-1, and ubc-18 pha-1 double mutants. SUP-35, which contains C2H2-type Zn-finger domains as well as a conserved RMD-like motif, showed a dynamic pattern of subcellular localization during embryogenesis. We find that mutations in sup-35 specifically suppress hypomorphic alleles of pha-1 and that SUP-35, acting genetically upstream of SUP-36 and SUP-37, negatively regulates pha-1 transcription. We further demonstrate that LIN-35, a transcriptional repressor, and UBC-18-ARI-1, a complex involved in ubiquitin-mediated proteolysis, negatively regulate SUP-35 abundance through distinct mechanisms. We also show that HCF-1, a C. elegans homolog of host cell factor 1, functionally antagonizes LIN-35 in the regulation of sup-35. Our cumulative findings piece together the components of a novel regulatory network that includes LIN-35/Rb, which functions to control organ morphogenesis. Our results also shed light on general mechanisms that

  20. Efeitos do Tai Chi Pai Lin no uso de medicamentos na Prefeitura de São Paulo

    Directory of Open Access Journals (Sweden)

    Luci Lurico Oi

    2012-06-01

    Full Text Available Introdução: Tai Chi Pai Lin é um conjunto de práticas corporais e meditativas da Medicina Tradicional Chinesa integrado por treinamentos de automassagem, meditação taoísta e sequências de movimentos suaves, circulares e lentos que promovem a flexibilidade, o relaxamento e o equilíbrio emocional.Dentre os benefícios do Tai Chi descritos na literatura pode-se ressaltar a redução de risco cardiovascular através da diminuição da pressão arterial e desempenho aeróbico (Taylor-Pilliae, 2006, justificando sua adoção entre as estratégias para prevenção e controle das Doenças e Agravos Não Transmissíveis (DANT. Doenças isquêmicas do coração, associadas à obesidade, depressão e estresse, são a primeira causa de morte na Coordenadoria Regional de Saúde Centro-Oeste (CRS CO, de acordo com dados da Coordenação de Epidemiologia e Informação (CEINFO, 2006. Nesta pesquisa investigamosrelações entre a prática de Tai Chi Pai Line o uso de medicamentos. Objetivos: Avaliar os efeitos da prática do Tai Chi Pai Lin em relação ao uso de medicamentos pelos usuários das unidades de saúde da CRS CO. Método: Foram selecionados randomicamente 75 usuários de prática de Tai Chi Pai Lin dos diversos serviços de saúde pública da CRS CO da cidade de São Paulo. Eles responderam questionários sobre o uso de medicamentos e indicaram alterações atribuídas à esta prática. A análise estatística foi realizada através dos programas Epi-Info e SPSS. Resultados: A percepção referida desta população em relação ao uso de medicamentos após a prática do Tai Chi Pai Lin mostrou: dos 12,70% que referiram utilizar antiinflamatório, 66,70% referiram diminuição do uso deste medicamento; dos 16,40% que referiram utilizar calmante, 60% referiram diminuição do uso deste medicamento; dos 14,50% que referiram utilizar antidepressivo, 55,60% referiram diminuição do uso deste medicamento edos 34,50% que referiram utilizar

  1. [Heavy metal pollution characteristics and ecological risk analysis for soil in Phyllostachys praecox stands of Lin'an].

    Science.gov (United States)

    Fang, Xiao-bo; Shi, Han; Liao, Xin-feng; Lou, Zhong; Zhou, Lyu-yan; Yu, Hai-xia; Yao, Lin; Sun, Li-ping

    2015-06-01

    An investigation was carried out in an attempt to reveal the characteristics of heavy metals contamination in the soils of Phyllostachys praecox forest in Lin' an. Based on the concentrations of Hg, As, Cu, Pb, Zn, Cd, Cr, Ni, Co and Mn in 160 topsoil samples, the pollution status and ecological risks of heavy metals in the soils were assessed by single factor pollution index, Nemerow integrated pollution index and Hankanson potential ecological risk index. The spatial variability of heavy metal concentrations in the soils closely related to the distribution of traffic, industrial and livestock pollution sources. The average concentrations of Hg, As, Cu, Pb, Zn, Cd, Cr, Ni, Co and Mn in the soils were 0.16, 7.41, 34.36, 87.98, 103.98, 0.26, 59.12, 29.56, 11.44 and 350.26 mg · kg(-1), respectively. Pb, Cd, Zn and Cu concentrations were as 2.89, 1.70, 1.12 and 1.12 times as the background values of soil in Zhejiang Province, respectively. But their concentrations were all lower than the threshold values of the National Environmental Quality Standard for Soil (GB 15618-1995). The average single factor pollution index revealed that the level of heavy metal pollution in the soils was in order of Pb>Cd>Cu= Zn>Hg>As>Ni>Co>Cr>Mn. Pb pollution was of moderate level while Cd, Cu and Zn pollutions were slight. There was no soil pollution caused by the other heavy metals. However, the Nemerow integrated pollution index showed that all the 160 soil samples were contaminated by heavy metals to a certain extent. Among total 160 soil samples, slight pollution level, moderate pollution level and heavy pollution level accounted for 55.6%, 29.4% and 15.0%, respectively. The average single factor potential ecological risk index (Er(i)) implied that the potential ecological risk related to Cd reached moderate level, while the others were of slight level. Furthermore, Cd and Hg showed higher potential ecological risk indices which reached up to 256.82 and 187.33 respectively

  2. A MULHER NEGRA E AS RELAÇÕES DE GÊNERO EM MENINO DE ENGENHO DE JOSÉ LINS DO REGO THE BLACK WOMAN AND GENDER RELATIONS IN MENINO DE ENGENHO BY JOSÉ LINS DO REGO

    Directory of Open Access Journals (Sweden)

    Zélia Monteiro Bora ; Marina Rodrigues de Oliveira

    2011-02-01

    Full Text Available Os romances do ciclo da cana-de-açúcar, do escritor paraibano José Lins do Rego (1901-1957 e a sua relação com a sociedade e a cultura destacam-se enquanto abordagens ficcionais, através das quais o escritor buscou representar aspectos relevantes para o entendimento das relações de gênero no Nordeste, no começo do século vinte. Tal representação, indiscutivelmente, reflete a perspectiva de um narrador profundamente marcado pelo lugar privilegiado de onde narra e de sua condição existencial, como o neto de um senhor de engenho. Diante desses aspectos, propomo- nos a analisar brevemente as implicações dessa perspectiva sobre a construção simbólica da personagem negra representada no romance. Para tanto, serão utilizados como referenciais críticos, além do citado romance, os estudos de Zagury (1982, Albuquerque Jr. (1999, Azevedo (1996, 2007, Freyre (2006 Chaguri (2009, Schwarz (2008 e Raboni (2010.The so called sugar cane cycle novels by the Parahyban writer Jose Lins do Rego (1901-197 and its relationship with society and culture constitute themselves as fictional approaches through which the writer sought to represent aspects to the understanding of gender relations in the Northeast of Brazil in the early twentieth century. Such representation, undoubtedly reflects the perspective of a narrator deeply marked by the privileged place from which he narrates and his existential condition, as the son of a plantation owner. Given these aspects, we propose to examine briefly the implications of his perspective on the symbolic construction of the black woman characteres represented in the novel. The following

  3. Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549.

    Science.gov (United States)

    Liu, Wei-Lun; Chang, Jia-Ming; Chong, Inn-Wen; Hung, Yi-Li; Chen, Yung-Hsiang; Huang, Wen-Tsung; Kuo, Hsuan-Fu; Hsieh, Chong-Chao; Liu, Po-Len

    2017-06-03

    Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene LIN28A as well as matrix metalloproteinase (MMP) 2 and MMP9 in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, LIN28A level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro.

  4. Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549

    Directory of Open Access Journals (Sweden)

    Wei-Lun Liu

    2017-06-01

    Full Text Available Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene LIN28A as well as matrix metalloproteinase (MMP 2 and MMP9 in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, LIN28A level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro.

  5. Paclitaxel-sensitization enhanced by curcumin involves down-regulation of nuclear factor-κB and Lin28 in Hep3B cells.

    Science.gov (United States)

    Zhou, Mingjie; Li, Zhaohui; Han, Ziwu; Tian, Nan

    2015-01-01

    Although paclitaxel is an effective chemotherapeutic drug used in the treatment of many tumors, hepatoma cells, in particular, are known to be highly resistant to it. Previously, we discovered that Lin28 was closely associated with resistance to paclitaxel in Hep3B cells. The nuclear factor-kappa B (NF-κB) transcription factor, which plays an important role in tumor survival, directly activates Lin28 expression through a binding site on the first intron. Curcumin, a non-toxic anti-inflammatory agent, inhibits NF-κB activity in vitro. In this study, we reported that a combination of curcumin and paclitaxel exhibited synergistic anti-proliferative and pro-apoptosis effects on Hep3B cells, and curcumin down-regulated paclitaxel-induced enhanced expression of Lin28 and NF-κB activation. Furthermore, our results revealed that curcumin reduced Lin28 levels via mechanisms directly mediated by inhibition of NF-κB activity. These mechanism-based observations evidence that curcumin enhances the sensitivity of hepatoma cells to paclitaxe, and strongly support the notion that paclitaxel in combination with curcumin may provide a superior therapeutic index for HCC chemotherapy.

  6. Sevoflurane inhibits embryonic stem cell self-renewal and subsequent neural differentiation by modulating the let-7a-Lin28 signaling pathway.

    Science.gov (United States)

    Yi, Xiuwen; Cai, Yirong; Zhang, Nan; Wang, Qingxiu; Li, Wenxian

    2016-08-01

    The commonly used inhalational anesthetic, sevoflurane, can cause toxicity to the central nervous system of the developing fetus. Lin28 has been reported to regulate let-7a, thereby modulating embryo development, neurodegeneration, and even neuron-related tumorigenesis. We demonstrate that pregnant mice receiving sevoflurane treatment during the early stage of pregnancy give birth to fewer offspring presenting a lower birth weight. We have also treated mouse embryonic stem cells (mESCs) with sevoflurane for 6 h and determined that mESCs self-renewal is repressed, and that differentiation is initiated earlier than in controls. We have induced neural differentiation in the treated mESCs and determined that their neurogenesis is weakened. Furthermore, sevoflurane upregulates the level of let-7a, which might repress mESC self-renewal by directly targeting the Lin28 3'-untranslated region. Lin28 overexpression attenuates the influence of sevoflurane or of let-7a on the self-renewal of mESCs and their subsequent neural differentiation. The let-7a inhibitor also abolishes the influence of sevoflurane. Thus, the let-7a-Lin28 pathway is involved in the sevoflurane-induced inhibition of ESC self-renewal and subsequent neurogenesis. Our study demonstrates the molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on the safe and reasonable usage of other inhalational anesthetics.

  7. Influences of LIN-12/Notch and POP-1/TCF on the Robustness of Ventral Uterine Cell Fate Specification in Caenorhabditis elegans Gonadogenesis.

    Science.gov (United States)

    Sallee, Maria D; Aydin, Taner; Greenwald, Iva

    2015-10-19

    The prospective ventral uterus of the hermaphrodite gonad primordium consists of two pairs of sister cells, with each pair consisting of a proximal "α" cell and a distal "β" cell. All four cells initially are competent to become the anchor cell (AC), a unique cell type that acts as the organizer of subsequent uterine and vulval development. However, the β cells soon lose this competence and always become ventral uterine precursor cells (VUs), whereas the α cells maintain their AC competence longer, until lin-12/Notch-mediated interactions between them specify one as the AC and the other as a VU. Here, we investigate this asymmetry in developmental potential and VU fate specification between the α and β sister cells. We find evidence that lin-12 activity contributes to the robustness of βVU fate at elevated temperature, that the Caenorhabditis elegans Notch paralog glp-1 is not functionally redundant with lin-12 in specifying βVU fate, and that the activity of POP-1, the sole C. elegans TCF ortholog, influences βVU fate. We propose a model for how Wnt and LIN-12/Notch signaling together lead to robust specification of the βVU fate. Copyright © 2015 Sallee et al.

  8. The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells.

    Science.gov (United States)

    Copley, Michael R; Babovic, Sonja; Benz, Claudia; Knapp, David J H F; Beer, Philip A; Kent, David G; Wohrer, Stefan; Treloar, David Q; Day, Christopher; Rowe, Keegan; Mader, Heidi; Kuchenbauer, Florian; Humphries, R Keith; Eaves, Connie J

    2013-08-01

    Mouse haematopoietic stem cells (HSCs) undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2(-/-) mice do not exhibit the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus, Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential.

  9. dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development.

    Science.gov (United States)

    Ceol, C J; Horvitz, H R

    2001-03-01

    The synthetic multivulva (synMuv) genes define two functionally redundant pathways that antagonize RTK/Ras signaling during Caenorhabditis elegans vulval induction. The synMuv gene lin-35 encodes a protein similar to the mammalian tumor suppressor pRB and has been proposed to act as a transcriptional repressor. Studies using mammalian cells have shown that pRB can prevent cell cycle progression by inhibiting DP/E2F-mediated transcriptional activation. We identified C. elegans genes that encode proteins similar to DP or E2F. Loss-of-function mutations in two of these genes, dpl-1 DP and efl-1 E2F, caused the same vulval abnormalities as do lin-35 Rb loss-of-function mutations. We propose that rather than being inhibited by lin-35 Rb, dpl-1 DP and efl-1 E2F act with lin-35 Rb in transcriptional repression to antagonize RTK/Ras signaling during vulval development.

  10. Dietary trans alpha-linolenic acid from deodorised rapeseed oil and plasma lipids and lipoproteins in healthy men: the TransLinE Study.

    NARCIS (Netherlands)

    Vermunt - Dongen, S.H.F.; Beaufrere, B.; Riemersma, R.A.; Sebedio, J.L.; Chardigny, J.M.; Mensink, R.P.

    2001-01-01

    : Br J Nutr 2001 Mar;85(3):387-92 Related Articles, Books, LinkOut Comment in: Br J Nutr. 2001 Mar;85(3):249-50. Dietary trans alpha-linolenic acid from deodorised rapeseed oil and plasma lipids and lipoproteins in healthy men: the TransLinE Study. Vermunt SH, Beaufrere B, Riemersma RA, Sebedio JL,

  11. Applying a Multiple Screening Program Aided by a Guideline-driven Computerized Decision Support System—A Pilot Experience in Yun-Lin, Taiwan

    Directory of Open Access Journals (Sweden)

    Jou-Wei Lin

    2007-01-01

    Conclusion: A computer-aided screening program driven by the US Preventive Services Task Force recommendations has been successfully implemented in Yun-Lin, Taiwan, and provided useful information about local epidemiology and implications for future health policy making. [J Formos Med Assoc 2007; 106(1:58-68

  12. Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers.

    Directory of Open Access Journals (Sweden)

    Åslaug Helland

    Full Text Available Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5 of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous

  13. Iodine Anions beyond -1: Formation of LinI (n = 2-5) and Its Interaction with Quasiatoms.

    Science.gov (United States)

    Botana, Jorge; Brgoch, Jakoah; Hou, Chunju; Miao, Maosheng

    2016-09-19

    Novel phases of LinI (n = 2, 3, 4, 5) compounds are predicted to form under high pressure using first-principles density functional theory and an unbiased crystal structure search algorithm. All of the phases identified are thermodynamically stable with respect to decomposition into elemental Li and the binary LiI at a relatively low pressure (≈20 GPa). Increasing the pressure to 100 GPa yields the formation of a high pressure electride where electrons occupy interstitial quasiatom (ISQ) orbitals. Under these extreme pressures, the calculated charge on iodine suggests the oxidation state goes beyond the conventional and expected -1 charge for the halogens. This strange oxidative behavior stems from an electron transfer going from the ISQ to I(-) and Li(+) ions as high pressure collapses the void space. The resulting interplay between chemical bonding and the quantum chemical nature of enclosed interstitial space allows this first report of a halogen anion beyond a -1 oxidation state.

  14. miR-125b promotes cell proliferation by directly targeting Lin28 in glioblastoma stem cells with low expression levels of miR-125b.

    Science.gov (United States)

    Wan, Yi; Sun, Guan; Wang, Zhimin; Guo, Jun; Shi, Lei

    2014-03-26

    MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. Our previous studies have revealed that miR-125b is a typical overexpressed miRNA in human primary glioblastoma stem cells (GSCs). Here, we report that miR-125b was also found to be significantly underexpressed in three primary GSCs. Characterization of the effects of the underexpressed miR-125b in GSCs showed that elevated levels of miR-125b inhibited cell growth and induced cell cycle arrest in the G0/G1 phase in vitro; a reduction in miR-125b levels had the opposite effect on tumour growth and progression. Further research into the underlying mechanism demonstrated that miR-125b acts by targeting Lin28 to regulate cell growth. Lin28 is highly expressed in human embryonic stem cells and glioblastomas. We showed that the specific repression of Lin28 results in decreased GSC proliferation, and that the overexpression of Lin28 accelerates cell proliferation. Our results highlight a novel molecular interaction between miR-125b and Lin28, and miR-125b may represent a potential novel therapeutic agent for targeting the proliferation of GSCs. In view of our previous research showing that miR-125b was overexpressed in GSCs and functioned as an oncogene, here our finding was not in agreement with our previous report, which implies that the personalized treatment on GSCs may be necessary and important.

  15. On the Design and Implementation of LIN -bus Data Monitor%汽车LIN总线数据监视器的设计与实现

    Institute of Scientific and Technical Information of China (English)

    沈万松

    2012-01-01

    LIN(Local Interconnect Network)总线是一种在汽车电子控制系统中已被普遍采用的低速、低成本的串行通讯网络。为了对基于LIN总线的分布式电子系统进行LIN总线信号测试和数据分析,对ELM633芯片的硬件电路进行设计,运用VC++软件编制实用软件,开发了操作简便的汽车LIN总线数据监视设备,由此可以成功实现对车辆LIN总线上全部信号的捕捉和采集。它的使用对LIN总线信号测试、数据分析和相关教学培训等工作具有一定的应用价值。%LIN ( Local Interconnect Network ) bus is a low - speed, low - cost serial communication network which has been widely used in automobile electronic control system. In order to test and analyze the signal that is based on LIN bus distributed electronic systems, the author has developed easy - operated automotive LIN bus data monitoring equipment by the designing of ELM633 chip hardware circuit and the programming of applying software via using VC + + software, so the capture and collection of LIN bus signal can be successfully a- chieved, which has highly valuable application in LIN bus signal testing, data analysis and related teaching and training work.

  16. The TRIM-NHL protein LIN-41 and the OMA RNA-binding proteins antagonistically control the prophase-to-metaphase transition and growth of Caenorhabditis elegans oocytes.

    Science.gov (United States)

    Spike, Caroline A; Coetzee, Donna; Eichten, Carly; Wang, Xin; Hansen, Dave; Greenstein, David

    2014-12-01

    In many animals, oocytes enter meiosis early in their development but arrest in meiotic prophase I. Oocyte growth, which occurs during this arrest period, enables the acquisition of meiotic competence and the capacity to produce healthy progeny. Meiotic resumption, or meiotic maturation, involves the transition to metaphase I (M phase) and is regulated by intercellular signaling and cyclin-dependent kinase activation. Premature meiotic maturation would be predicted to diminish fertility as the timing of this event, which normally occurs after oocyte growth is complete, is crucial. In the accompanying article in this issue, we identify the highly conserved TRIM-NHL protein LIN-41 as a translational repressor that copurifies with OMA-1 and OMA-2, RNA-binding proteins redundantly required for normal oocyte growth and meiotic maturation. In this article, we show that LIN-41 enables the production of high-quality oocytes and plays an essential role in controlling and coordinating oocyte growth and meiotic maturation. lin-41 null mutants display a striking defect that is specific to oogenesis: pachytene-stage cells cellularize prematurely and fail to progress to diplotene. Instead, these cells activate CDK-1, enter M phase, assemble spindles, and attempt to segregate chromosomes. Translational derepression of the CDK-1 activator CDC-25.3 appears to contribute to premature M-phase entry in lin-41 mutant oocytes. Genetic and phenotypic analyses indicate that LIN-41 and OMA-1/2 exhibit an antagonistic relationship, and we suggest that translational regulation by these proteins could be important for controlling and coordinating oocyte growth and meiotic maturation.

  17. A Human Lin(-) CD123(+) CD127(low) Population Endowed with ILC Features and Migratory Capabilities Contributes to Immunopathological Hallmarks of Psoriasis.

    Science.gov (United States)

    Mora-Velandia, Luz María; Castro-Escamilla, Octavio; Méndez, Andrés González; Aguilar-Flores, Cristina; Velázquez-Avila, Martha; Tussié-Luna, María Isabel; Téllez-Sosa, Juan; Maldonado-García, César; Jurado-Santacruz, Fermín; Ferat-Osorio, Eduardo; Martínez-Barnetche, Jesus; Pelayo, Rosana; Bonifaz, Laura C

    2017-01-01

    Innate lymphoid cells (ILC) are members of a heterogeneous family with a lymphoid origin that mimics the T helper (Th) cytokine profile. ILC are involved in early effector cytokine-mediated responses during infections in peripheral tissues. ILC also play an important role in chronic skin inflammatory diseases, including psoriasis. Although classical ILC express CD127, it has been recently reported that the presence of non-classical CD127(-) ILC populations and an early ILC precursor (EILP) CD127(low). ILC development has predominately been investigated in mouse models. However, in humans, different transcription factors have been described for ILC identification. NFIL3 (nuclear factor, IL-3 regulated) is crucial for ILC development in response to IL-7. CD123 (IL-3Rα) is usually used to exclude basophils during ILC identification, however, it is unknown if in response to IL-3, NFIL3 could be relevant to induce ILC features in Lin(-) CD123(+) populations in addition, is also unknown whether peripheral blood (PB) population with ILC features may have skin-homing potential to participate in skin inflammatory chronic diseases. Here, we report a Lin(-) CD123(+) CD127(low) CD7(+) CLA(+) population that share some phenotypic properties with basophils, but expresses several transcription factors for ILC commitment such as inhibitor of DNA binding 2 (Id2), NFIL3, promyelocytic leukemia zinc finger (PLZF), thymocyte selection-associated high-mobility group box protein (TOX), and T cell factor-1 (TCF-1). In addition, this population expresses different ILC markers: CD132, CD90, CD161, α4 integrin, c-Kit, CRTH2, AhR, and IL-23R. IL-3 prevents apoptosis and increases their NFIL3, TOX, and PLZF expression. In PB, the CD123(+) CD127(low) population is predominantly a conspicuous population that expresses T-bet and RORγt. The Lin(-) CD123(+) CD127(low) population in PB has a limited Th type cytokine expression and highly expresses IL-8. The Lin(-) CD123(+) CD127(low) population

  18. Perturbation of MicroRNA-370/Lin-28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma.

    Science.gov (United States)

    Xu, Wen-Ping; Yi, Min; Li, Qian-Qian; Zhou, Wei-Ping; Cong, Wen-Ming; Yang, Yuan; Ning, Bei-Fang; Yin, Chuan; Huang, Zhao-Wei; Wang, Jian; Qian, Hui; Jiang, Cai-Feng; Chen, Yue-Xiang; Xia, Chun-Yan; Wang, Hong-Yang; Zhang, Xin; Xie, Wei-Fen

    2013-12-01

    MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer-associated genomic region. However, the role of miR-370 in malignances remains controversial. Here, we report that miR-370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated that miR-370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR-370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA-binding protein, LIN28A, was identified as a direct functional target of miR-370, which, in turn, blocked the biogenesis of miR-370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR-370 on migration and invasion of HCC cells by post-transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF-κB) pathway. Interleukin-6 (IL-6), a well-known NF-κB downstream inflammatory molecule, reduced miR-370 but increased LIN28A levels in HCC. Furthermore, miR-370 levels were inversely correlated with LIN28A and IL-6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL-6 expression in human HCC samples. Interestingly, reduction of miR-370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. These data demonstrate the involvement of a novel regulatory circuit consisting of miR-370, LIN28A, RelA/p65 and IL-6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment. © 2013 by the American Association for the Study of Liver Diseases.

  19. Crystal structures of MW1337R and lin2004: Representatives of a novel protein family that adopt a four-helical bundle fold

    Energy Technology Data Exchange (ETDEWEB)

    Kozbial, Piotr; Xu, Qingping; Chiu, Hsiu-Ju; McMullan, Daniel; Krishna, S. Sri; Miller, Mitchell D.; Abdubek, Polat; Acosta, Claire; Astakhova, Tamara; Axelrod, Herbert L.; Carlton, Dennis; Clayton, Thomas; Deller, Marc; Duan, Lian; Elias, Ylva; Elsliger, Marc-André; Feuerhelm, Julie; Grzechnik, Slawomir K.; Hale, Joanna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K.; Klock, Heath E.; Knuth, Mark W.; Koesema, Eric; Kumar, Abhinav; Marciano, David; Morse, Andrew T.; Murphy, Kevin D.; Nigoghossian, Edward; Okach, Linda; Oommachen, Silvya; Reyes, Ron; Rife, Christopher L.; Spraggon, Glen; Trout, Christina V.; ban den Bedem, Henry; Weekes, Dana; White, Aprilfawn; Wolf, Guenter; Zubieta, Chloe; Hodgson, Keith O.; Wooley, John; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A. (Scripps); (SSRL); (JCSG); (UCSD); (Burnham)

    2009-08-28

    To extend the structural coverage of proteins with unknown functions, we targeted a novel protein family (Pfam accession number PF08807, DUF1798) for which we proposed and determined the structures of two representative members. The MW1337R gene of Staphylococcus aureus subsp. aureus Rosenbach (Wood 46) encodes a protein with a molecular weight of 13.8 kDa (residues 1-116) and a calculated isoelectric point of 5.15. The lin2004 gene of the nonspore-forming bacterium Listeria innocua Clip11262 encodes a protein with a molecular weight of 14.6 kDa (residues 1-121) and a calculated isoelectric point of 5.45. MW1337R and lin2004, as well as their homologs, which, so far, have been found only in Bacillus, Staphylococcus, Listeria, and related genera (Geobacillus, Exiguobacterium, and Oceanobacillus), have unknown functions and are annotated as hypothetical proteins. The genomic contexts of MW1337R and lin2004 are similar and conserved in related species. In prokaryotic genomes, most often, functionally interacting proteins are coded by genes, which are colocated in conserved operons. Proteins from the same operon as MW1337R and lin2004 either have unknown functions (i.e., belong to DUF1273, Pfam accession number PF06908) or are similar to ypsB from Bacillus subtilis. The function of ypsB is unclear, although it has a strong similarity to the N-terminal region of DivIVA, which was characterized as a bifunctional protein with distinct roles during vegetative growth and sporulation. In addition, members of the DUF1273 family display distant sequence similarity with the DprA/Smf protein, which acts downstream of the DNA uptake machinery, possibly in conjunction with RecA. The RecA activities in Bacillus subtilis are modulated by RecU Holliday-junction resolvase. In all analyzed cases, the gene coding for RecU is in the vicinity of MW1337R, lin2004, or their orthologs, but on a different operon located in the complementary DNA strand. Here, we report the crystal structures

  20. 《法苑珠林校注》校勘补遗%A Supplement to Collation and Annotation of Fa Yuan Zhu Lin

    Institute of Scientific and Technical Information of China (English)

    范崇高

    2016-01-01

    Fa Yuan Zhu Lin is one of the most important Buddhist literature. Collation and Annotation of Fa Yuan Zhu Lin publi shed by Zhonghua Book Company, is an excellent book on the collation of ancient books. However, some sentences are misleadi ng due to missing collation. This paper aims at supplementing collation suggestions to seventeen sentences in this book.%《法苑珠林》是研究佛教文化最为重要的文献之一,中华书局出版的《法苑珠林校注》是一部上乘的古籍整理著作,但其中偶有一些词句因为失校而影响文意的正确理解,今提出16条校勘意见,供研究者参考。

  1. Initial real world experience with a novel insertable (Reveal LinQ(@Medtronic)) compared to the conventional (Reveal XT(@Medtronic)) implantable loop recorder at a tertiary care center - Points to ponder!

    Science.gov (United States)

    Gunda, Sampath; Reddy, Yeruva Madhu; Pillarisetti, Jayasree; Koripalli, Sandeep; Jeffery, Courtney; Swope, Jeanine; Atkins, Donita; Bommana, Sudharani; Emert, Martin P; Pimentel, Rhea; Dendi, Raghuveer; Berenbom, Loren D; DiBiase, Luigi; Natale, Andrea; Lakkireddy, Dhanunjaya

    2015-07-15

    Limited data is available regarding the novel Reveal LinQ (LinQ) which is a new generation implantable loop recorders (ILRs). We performed a prospective, observational study of all consecutive patients undergoing conventional (Reveal XT; XT) and LinQ devices at our institution between January 2012 and December 2014. A total of 217 patients underwent ILR implantation. XT was implanted in 105 and LinQ in 112 patients. There were no significant differences in baseline characteristics between the two groups. LinQ implantation using the manufacturer's technique termed, "manufacturer's method" group had significantly higher incidence of pocket infection compared to XT (6/50, 12% vs 3/105, 3%, p=0.032). With modifications to the LinQ implantation technique (using a conventional scalpel and placing a suture when needed to the incision) termed "modified method" group, the rate of infection has decreased significantly compared to "manufacturer's method group" (0/62, 0% vs 6/50, 12%, p=0.004) (Table 3). In multivariate regression analysis, the only independent predictors of infection were younger age (OR 0.95; p=0.04), insertion of LinQ device (OR 30.02; p=0.006) and procedure time (OR 1.07; p=0.03). In our single-center, prospective, observational study we found that with the current implantable techniques, the novel insertable LinQ device is associated with increased risk of complications. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Lattice dynamics and electronic structure of energetic solids LiN3 and NaN3: A first principles study

    OpenAIRE

    Babu, K Ramesh; Vaitheeswaran, G.

    2013-01-01

    We report density functional theory calculations on the crystal structure, elastic, lattice dynamics and electronic properties of iso-structural layered monoclinic alkali azides, LiN3 and NaN3. The effect of van der Waals interactions on the ground- state structural properties is studied by using various dispersion corrected density functionals. Based on the equilibrium crystal structure, the elastic constants, phonon dispersion and phonon density of states of the compounds are calculated. Th...

  3. Lin- CD34hi CD117int/hi FcεRI+ cells in human blood constitute a rare population of mast cell progenitors.

    Science.gov (United States)

    Dahlin, Joakim S; Malinovschi, Andrei; Öhrvik, Helena; Sandelin, Martin; Janson, Christer; Alving, Kjell; Hallgren, Jenny

    2016-01-28

    Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage-negative (Lin(-)) CD34(hi) CD117(int/hi) FcεRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin β7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A messenger RNA transcripts were detected by quantitative reverse transcription-polymerase chain reaction. Altogether, we propose that the Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood mast cell progenitors than asthmatics with normal lung function.

  4. Virtual Visit to the ATLAS Control Room by Laboratoire de l`Accélérateur Linéaire in Orsay

    CERN Multimedia

    2013-01-01

    The `Laboratoire de l`Accélérateur Linéaire` (LAL, CNRS/IN2P3 and University Paris Sud) is a major French laboratory for basic science, located on the Orsay campus. Its core research field is particle physics but the lab is also involved in several other fields: astroparticles, ultra-high energetic phenomena in the Universe, astrophysics, cosmology and R&D on accelerators.

  5. WATER QUALITY EVALUATION IN MICROWATERSHED OF THE CAMPESTRE STREAM (LINS, SÃO PAULO STATE, BRAZIL LINS TOWN (SP = AVALIAÇÄO DA QUALIDADE DA ÁGUA NA MICROBACIA DO CÓRREGO CAMPESTRE NO MUNICIPIO DE LINS (SP

    Directory of Open Access Journals (Sweden)

    Sérgio Luís de Carvalho

    2009-01-01

    Full Text Available This work aims to present the water quality assessment of Campestre´s Stream watershed inserted in Lins town limit, in the São Paulo’ State, during the period between mars and december 2002. The water was sampled at seven points of this watershed, and then the physical, chemical and biological parameters were analysed in the university laboratory. Through the seasonality and correlation of physical, chemical and biological parameters with the results of Water Quality Rate (WQR and the researches on field, were possible to verify that the effects of the main antropics activities (stream channel erosion beside the complete inexistence of riparian zone developed around these stream caused the nutrients elevation (phosphorus and nitrogen and the increase of coliform concentration levels mainly in the urban collection points that contributed to the watershed degradation. = O trabalho teve como objetivo proceder à avaliação da qualidade da água na Microbacia Hidrográfica do Córrego Campestre, Município Lins, Estado de São Paulo, no período de março a dezembro de 2002, e o seu estado de degradação. Foram coletadas amostras de água em sete pontos da Microbacia e realizados ensaios de parâmetros físico-químicos e biológicos. A partir dos resultados do Índice de Qualidade de Água (IQA e das análises de correlação e sazonalidade dos parâmetros físicos, químicos e biológicos combinados com levantamentos de campo, constatou-se que as atividades antrópicas provocaram a elevação dos teores de nutrientes (fósforo e nitrogênio e aumento dos níveis de concentrações de coliformes fecais, principalmente nos pontos de coleta que ficam dentro do perímetro urbano, onde se encontram prováveis lançamentos de esgotos clandestinos contribuindo para a degradação da microbacia estudada.

  6. Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma.

    Science.gov (United States)

    Hayashi, S; Tanaka, J; Okada, S; Isobe, T; Yamamoto, G; Yasuhara, R; Irie, T; Akiyama, C; Kohno, Y; Tachikawa, T; Mishima, K

    2013-05-01

    Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Building a Rapid Learning Health Care System for Oncology: Why CancerLinQ Collects Identifiable Health Information to Achieve Its Vision.

    Science.gov (United States)

    Shah, Alaap; Stewart, Andrew K; Kolacevski, Andrej; Michels, Dina; Miller, Robert

    2016-03-01

    The ever-increasing volume of scientific discoveries, clinical knowledge, novel diagnostic tools, and treatment options juxtaposed with rising costs in health care challenge physicians to identify, prioritize, and use new information rapidly to deliver efficient and high-quality care to a growing and aging patient population. CancerLinQ, a rapid learning health care system in oncology, is an initiative of the American Society of Clinical Oncology and its Institute for Quality that addresses these challenges by collecting information from the electronic health records of large numbers of patients with cancer. CancerLinQ is first and foremost a quality measurement and reporting system through which oncologists can harness the depth and power of their patients' clinical records and other data to assess, monitor, and improve the care they deliver. However, in light of privacy and security concerns with regard to collection, use, and disclosure of patient information, this article addresses the need to collect protected health information as defined under the Health Insurance Portability and Accountability Act of 1996 to drive rapid learning through CancerLinQ.

  8. Drosophila Lin-7 is a component of the Crumbs complex in epithelia and photoreceptor cells and prevents light-induced retinal degeneration.

    Science.gov (United States)

    Bachmann, André; Grawe, Ferdi; Johnson, Kevin; Knust, Elisabeth

    2008-03-01

    The Drosophila Crumbs protein complex is required to maintain epithelial cell polarity in the embryo, to ensure proper morphogenesis of photoreceptor cells and to prevent light-dependent retinal degeneration. In Drosophila, the core components of the complex are the transmembrane protein Crumbs, the membrane-associated guanylate kinase (MAGUK) Stardust and the scaffolding protein DPATJ. The composition of the complex and some of its functions are conserved in mammalian epithelial and photoreceptor cells. Here, we report that Drosophila Lin-7, a scaffolding protein with one Lin-2/Lin-7 (L27) domain and one PSD-95/Dlg/ZO-1 (PDZ) domain, is associated with the Crumbs complex in the subapical region of embryonic and follicle epithelia and at the stalk membrane of adult photoreceptor cells. DLin-7 loss-of-function mutants are viable and fertile. While DLin-7 localization depends on Crumbs, neither Crumbs, Stardust nor DPATJ require DLin-7 for proper accumulation in the subapical region. Unlike other components of the Crumbs complex, DLin-7 is also enriched in the first optic ganglion, the lamina, where it co-localizes with Discs large, another member of the MAGUK family. In contrast to crumbs mutant photoreceptor cells, those mutant for DLin-7 do not display any morphogenetic abnormalities. Similar to crumbs mutant eyes, however, DLin-7 mutant photoreceptors undergo progressive, light-dependent degeneration. These results support the previous conclusions that the function of the Crumbs complex in cell survival is independent from its function in photoreceptor morphogenesis.

  9. TRA-1/GLI controls the expression of the Hox gene lin-39 during C. elegans vulval development.

    Science.gov (United States)

    Szabó, Emese; Hargitai, Balázs; Regos, Agnes; Tihanyi, Borbála; Barna, János; Borsos, Eva; Takács-Vellai, Krisztina; Vellai, Tibor

    2009-06-15

    The vulva of the Caenorhabditis elegans hermaphrodite develops from a subset of six vulval precursor cells (VPCs) by the combined effect of the Ras, Wingless and Notch signaling cascades, and of three redundant synMuv (synthetic Multivulva) pathways grouped into classes A, B and C. Here we show that signaling via the GLI- (Glioma-associated protein) like transcription factor TRA-1, which is the terminal regulator of the C. elegans sex determination cascade, is a newly discovered pathway specifying vulval cell fates. We found that TRA-1 accumulates in, and regulates the fusion process of, cells (including the VPCs and hypodermal cells) involved in vulval patterning. TRA-1 also influenced the expression of the Hox gene lin-39, a central regulator of vulval development. Furthermore, inactivation of tra-1, which transforms animals with hermaphrodite-specific karyotype into males, promoted vulval induction in synMuv A, but not in synMuv B, mutant background. This implies that TRA-1 interacts with the class B synMuv genes, many of which are involved in chromatin-mediated transcriptional repression of cell proliferation. These results may help to understand how compromised GLI activity in humans leads to cancer. Together, we suggest that the GLI protein family involved in several key developmental processes in both invertebrates and vertebrates regulates somatic cell fates through influencing, at least in part, the expression of specific Hox genes.

  10. Flowing Within the Text:A Discussion on He Lin's Explanation of Zhu Xi's Method of intuition

    Institute of Scientific and Technical Information of China (English)

    Zhang Xianglong

    2006-01-01

    The author examines He Lin's interpretation of Zhu Xi's method of intuition from a phenomenological-hermeneutical perspective and by exposing Zhu's philosophical presuppositions.In contrast with Lu Xiangshan's intuitive method,Zhu Xi's method of reading classics advocates "emptying your heart and flowing with the text" and,in this spirit,explains the celebrated "exhaustive investigation on the principles of things (ge wu qiong li)." "Text," according to Zhu,is therefore not an object in ordinary sense but a "contextual region" or "sensible pattern" that,when merged with the reader,generates meanings.Furthermore,by discussing the related doctrines of Lao Zi,Zhuang Zi,Hua-Yan Buddhism,Zhou Dunyi,and Zhu Xi's own "One principle with many manifestations (li yi fen shu)," the author identifies the philosophical preconditions of Zhu's method.Based on this analysis,the author goes on to illustrate Zhu's understanding of "observing potential yet unapparent pleasure,anger,sorrow and happiness" and "maintaining a serious attitude (zhu jing)."

  11. 林则徐与海神祭祀%Lin Ze-xu and Sacrifice to the God of Sea

    Institute of Scientific and Technical Information of China (English)

    朱慧

    2013-01-01

    Lin Ze-xu is a progressive thinker and great patriot in the history of modern China, and is a devout theist at the same time. He led the splendid action of destroying opium stocks in Humen Beach, which is a glorious page in Chinese history, moreover, he left us a famous immortal literary piece, a Funeral Oration to the God of Sea, declaring to the world our Chinese people’s decision to ban opium and refuse drugs.%林则徐是中国近代进步的思想家和伟大的爱国主义者,同时他也是一位虔诚的有神论者。他领导的轰轰烈烈的虎门销烟在中国历史上留下了光辉的一页,也为我们留下了不朽名篇《祭海神文》,向世界宣告了中国禁烟和拒毒的决心。

  12. Origin of the Galactic Center S-Stars: Gravitational Torques from Lin-Shu-Type Spiral Density Waves

    Science.gov (United States)

    Griv, Evgeny

    2010-02-01

    The supermassive ~4 × 106 M sun black hole at the Galactic center is surrounded by a parsec-scale star disk, with several thousands of dynamically relaxed, evolved, late-type CO absorption line stars and a small ~100 population of luminous O and Wolf-Rayet stars which move in approximately circular Keplerian orbits. These bluish in color massive O and Wolf-Rayet stars are very young with an estimated age of 6 ± 2 Myr. Another small group of roughly 20 young (blue B stars with the orbital periods as short as 15 years ("S-stars") follow eccentric, randomly oriented orbits well inside the disk stars. A model is proposed to explain the S-stars. Accordingly, the stars formed originally in the parsec-scale disk through Jeans' gravitational fragmentation of gas. The newly formed S-stars then migrated inward to the Galactic center via the torques exerted by Lin-Shu-type spiral density waves on the stars at an inner Lindblad resonance. The model explains both the number of observed S-stars orbiting the Galactic black hole within the nuclear (<0.05 pc) star cluster and the key property of the S-star orbits, namely, their high eccentricities.

  13. Just-in time system and climate change

    Energy Technology Data Exchange (ETDEWEB)

    Caceres, J.; Richards, D.

    1999-10-01

    The recent trends in freight transportation and its relationship with production and distribution were analyzed. This was done in an effort to help policy makers develop strategies to reduce greenhouse gas emissions and to develop a freight transportation system and a route system that is environmentally, economically and socially sustainable. One of the ways to find a solution is to restructure the overall industry organization and its link to transportation and the economy. However, this method is met with a lot of resistance by policy makers. Another method would be to find a way to delay or avoid restructuring; for example, by using unlimited greenhouse gas emissions trading. By doing so, emissions reductions would be targeted where they are most economically efficient. 18 refs., 1 fig.

  14. Justin Frankel,Winamp的反斗奇星

    Institute of Scientific and Technical Information of China (English)

    方茜

    2005-01-01

    Wnamp是他19岁时的杰作。他像Bll Gates一样年少得志,但却没有选择走Bill Gates那样的道路。他不断制造麻烦,但又不断地涌出奇思妙想,创造各种软件工具。

  15. 2599-IJBCS-Article-Arcadius Yves Justin A+

    African Journals Online (AJOL)

    hp

    L'évaluation du taux de reprise est de 96,35% pour les plants semés en pots contre. 94,44% pour ... sociales et environnementales (de Groot et al., 2010 ;. Ferraz et al., 2013). Dans ce cadre ...... AYJA est le porteur du projet, il a supervisé ...

  16. Dialoogid kohatusest / Justin Ions ; tõlkinud Katrin Kivimaa

    Index Scriptorium Estoniae

    Ions, Justin

    2009-01-01

    Rahvusvaheline näitus "thisPLACEd" ("Kohatute koht") Tallinna Linnagaleriis 1. märtsini. Kuraatorid Silvina Der-Meguerditchian ja Reet Varblane. Suur osa näitusel osalevatest kunstnikest on armeenia päritolu. Koostöösse on kaasatud Eestiga seotud kunstnikud Olga Jürgenson (elab Londonis) ja Eléonore de Montesquiou

  17. Justin Bieber:并不只是传奇

    Institute of Scientific and Technical Information of China (English)

    云崽子(文字); 西维亚(设计)

    2011-01-01

    刚刚发行的新书《第一步到永远:我的故事》向大家展示了一个更真实的贾斯汀·比伯,讲述了他从1994年出生以来的成长历程及动人故事。这个少年的传奇经历让他自己都无法相信,他说:“这本书讲述了我的世界改变有多大、多快。”

  18. Dialoogid kohatusest / Justin Ions ; tõlkinud Katrin Kivimaa

    Index Scriptorium Estoniae

    Ions, Justin

    2009-01-01

    Rahvusvaheline näitus "thisPLACEd" ("Kohatute koht") Tallinna Linnagaleriis 1. märtsini. Kuraatorid Silvina Der-Meguerditchian ja Reet Varblane. Suur osa näitusel osalevatest kunstnikest on armeenia päritolu. Koostöösse on kaasatud Eestiga seotud kunstnikud Olga Jürgenson (elab Londonis) ja Eléonore de Montesquiou

  19. A role of the LIN-12/Notch signaling pathway in diversifying the non-striated egg-laying muscles in C. elegans.

    Science.gov (United States)

    Hale, Jared J; Amin, Nirav M; George, Carolyn; Via, Zachary; Shi, Herong; Liu, Jun

    2014-05-15

    The proper formation and function of an organ is dependent on the specification and integration of multiple cell types and tissues. An example of this is the Caenorhabditis elegans hermaphrodite egg-laying system, which requires coordination between the vulva, uterus, neurons, and musculature. While the genetic constituents of the first three components have been well studied, little is known about the molecular mechanisms underlying the specification of the egg-laying musculature. The egg-laying muscles are non-striated in nature and consist of sixteen cells, four each of type I and type II vulval muscles and uterine muscles. These 16 non-striated muscles exhibit distinct morphology, location, synaptic connectivity and function. Using an RNAi screen targeting the putative transcription factors in the C. elegans genome, we identified a number of novel factors important for the diversification of these different types of egg-laying muscles. In particular, we found that RNAi knockdown of lag-1, which encodes the sole C. elegans ortholog of the transcription factor CSL (CBF1, Suppressor of Hairless, LAG-1), an effector of the LIN-12/Notch pathway, led to the production of extra type I vulval muscles. Similar phenotypes were also observed in animals with down-regulation of the Notch receptor LIN-12 and its DSL (Delta, Serrate, LAG-2) ligand LAG-2. The extra type I vulval muscles in animals with reduced LIN-12/Notch signaling resulted from a cell fate transformation of type II vulval muscles to type I vulval muscles. We showed that LIN-12/Notch was activated in the undifferentiated type II vulval muscle cells by LAG-2/DSL that is likely produced by the anchor cell (AC). Our findings provide additional evidence highlighting the roles of LIN-12/Notch signaling in coordinating the formation of various components of the functional C. elegans egg-laying system. We also identify multiple new factors that play critical roles in the proper specification of the different types

  20. Qualidade de um sistema latossolo-argissolo como receptor de efluentes no município de Lins(SP Quality of a latosol-argisol system in the county of Lins/SP, Brazil

    Directory of Open Access Journals (Sweden)

    Liliane Ibrahim

    2008-12-01

    Full Text Available Este trabalho objetivou caracterizar um sistema de solos, evidenciando a propriedades que possam esclarecer sua dinâmica e contribuir para a definição de critérios que condicionem a aptidão destes solos como receptores de efluentes. Trata-se de uma área experimental de estudos, contígua à Estação de Tratamento de Esgoto do município de Lins (SP, onde o efluente é gerado a partir do tratamento de esgoto por sistema de lagoas de estabilização. Os solos, situados ao longo de uma vertente com ligeira inclinação, foram caracterizados por meio de análises, morfológica, granulométrica, química, mineralógica e micromorfológica, realizadas em amostras coletadas em cinco trincheiras em toposseqüência. Os solos são desenvolvidos a partir dos sedimentos arenosos da Formação Adamantina (Grupo Bauru e constituem um sistema Latossolo - Argissolo onde a transição Bw - Bt ocorre lateralmente do topo para a base da vertente. Foram identificadas três fases pedogenéticas nesta associação de solos. A primeira, argiluviação e adensamento de partículas, responsável pela formação dos horizontes texturais, foi superposta pelos processos de latossolização e hidromorfismo, atuantes na dinâmica atual destes solos. Análises micromorfológicas mostraram tratar-se de solos com intensa porosidade, caracterizada pelo empilhamento dos grãos do esqueleto quartzoso amplamente predominante e pelo arranjo entre os microagregados granulares. A permeabilidade é ainda favorecida pela intensa ação da mesofauna. Os solos são distróficos e compostos por caulinita e óxidos de Fe na fração argilosa. Por constituírem um sistema frágil, a disposição de quaisquer tipos de resíduos nestes solos requer o monitoramento constante de suas propriedades, tanto para a manutenção, quanto para a recuperação da qualidade desta cobertura pedológica.The purpose of this study was the characterization of a soil system, focused on proprieties that

  1. 燕梦卿与林黛玉比较研究%Comparative Study about Yan Mengqing and Lin Daiyu

    Institute of Scientific and Technical Information of China (English)

    莫罗红

    2014-01-01

    Yan Mengqing and Lin Daiyu are two typical female characters in the history of Chinese fiction. They are perfect images of traditional Chinese lady which represents the author’s ideal. It suggests that the living beings are metaphor for human and those noble character of them reflects the purity of human nature, which suggest the two women’s destiny. By combining emotion and traditional ideas, the author also shows his appreciation on human nature .When it comes a sad ending that is about a premature death of the ladies, instead of giving a normal happy ending, it is an embodiment of the author’s new understandings towards life attitude. Besides, those stories of life and death appear that the author is positive about the good impact on kindness and caring.%燕梦卿和林黛玉是中国小说史上两个典型的女性形象,是中国传统淑女形象的理想化呈现。她们的身上寄托了作者的审美理想:以“草木”喻人,借物之高洁品质来写人之清净性情,并暗含人物的命运走向;情与礼的融合,表明作者对自然人性的欣赏;以早逝为结局的人生命运,打破了传统大团圆的书写模式,体现出作者对现实人生的种种思考和感悟,而不讳谈生死的写作态度则是作者肯定了死亡对美善的积极意义。

  2. 论林语堂的幽默文学观%On LIN Yu-tang's View of Humorous Literature

    Institute of Scientific and Technical Information of China (English)

    谢昭新

    2009-01-01

    林语堂发明了"幽默"一词,建构了他的幽默文学观.在"语丝"时期,将"幽默"看成是"真实的,宽容的,同情的人生观", 此间的散文,多在"真实"、真诚上面用力,讽刺力量较强."论语"、"人间世"时期的幽默则多从个人性灵上抒写闲适的情调,其幽默观中多带个人主义色彩,是"以自我为中心,以闲适为格调" 的自由主义的人生观.他的幽默观和幽默小品创作又特别重视幽默的审美价值,创造了滑稽、机警、俏皮、讽刺的"笑"的美感情趣.%LIN Yu-tang creates a new concept of humor in order to construct his literary thoughts. During the period when he writes for a magazine called "Yusi",he considers "humor" as "a sincere, tolerant and sympathetic view of life". As a result, his prose usually has sarcastic strength rooted in the real human life and his open heart. However, during the period when he edits magazines called "Lunyu" and "Renjianshi", his prose changes to express his personal spirit with a leisurely style. At this time, his view of humor inclined to individualism and liberalism. Besides, his thinking and writings on humor paid attention to the aesthetic value of humor, which includes farcicality, wittiness, naughtiness, irony and laugh.

  3. The human fetal lymphocyte lineage: identification by CD27 and LIN28B expression in B cell progenitors

    Science.gov (United States)

    McWilliams, Laurie; Su, Kuei-Ying; Liang, Xiaoe; Liao, Dongmei; Floyd, Serina; Amos, Joshua; Moody, M. Anthony; Kelsoe, Garnett; Kuraoka, Masayuki

    2013-01-01

    CD27, a member of the TNFR superfamily, is used to identify human memory B cells. Nonetheless, CD27+ B cells are present in patients with HIGM1 syndrome who are unable to generate GCs or memory B cells. CD27+IgD+ fetal B cells are present in umbilical cord blood, and CD27 may also be a marker of the human B1-like B cells. To define the origin of naïve CD27+IgD+ human B cells, we studied B cell development in both fetal and adult tissues. In human FL, most CD19+ cells coexpressed CD10, a marker of human developing B cells. Some CD19+CD10+ B cells expressed CD27, and these fetal CD27+ cells were present in the pro-B, pre-B, and immature/transitional B cell compartments. Lower frequencies of phenotypically identical cells were also identified in adult BM. CD27+ pro-B, pre-B, and immature/transitional B cells expressed recombination activating gene-1, terminal deoxynucleotidyl transferase and Vpre-B mRNA comparably to their CD27− counterparts. CD27+ and CD27− developing B cells showed similar Ig heavy chain gene usage with low levels of mutations, suggesting that CD27+ developing B cells are distinct from mutated memory B cells. Despite these similarities, CD27+ developing B cells differed from CD27− developing B cells by their increased expression of LIN28B, a transcription factor associated with the fetal lymphoid lineages of mice. Furthermore, CD27+ pro-B cells efficiently generated IgM+IgD+ immature/transitional B cells in vitro. Our observations suggest that CD27 expression during B cell development identifies a physiologic state or lineage for human B cell development distinct from the memory B cell compartment. PMID:23901121

  4. Comments on "place and human development" by Paul Shepard and Yi-Fu Tuan's "experience and appreciation"

    Science.gov (United States)

    Florence C. Ladd

    1977-01-01

    Paul Shepard presents a dazzling array of profound ideas about the nature of the relationship between early developmental stages and places experienced in a variety of cultures. Shepard's analysis is related to the schema presented in Spivack's (1973) paper, in which he identifies some basic requirements of the human species and the environmental conditions...

  5. Characteristics of vertical ozone distribution in the lower troposphere in the Yangtze River Delta at Lin'an in the spring of 2001

    Institute of Scientific and Technical Information of China (English)

    ZHENG Xiangdong; CHAN Chuenyu; CUI Hong; QIN Yu; CHAN Loyan; ZHENG Yongguang; LEE Yusiang

    2005-01-01

    We analyzed vertical distributions of ozone (O3) in the lower troposphere (< 5 km above ground) at Lin'an (119.75°E, 30.30°N), Zhejiang Province using electrochemical concentration cell (ECC) ozonesonde data obtained from February 21 to April 13, 2001. The results showed that the vertical O3 distributions are controlled by metrological conditions and the characteristics of O3 profiles are related to those of wet bulb potential temperature and wind field. O3 below 2 km showed that the strongest variability and enhanced O3 mixing ratios were associated with easterly winds that blow pollutants from the upwind source region of the Yangtze River Delta (YRD) region. Vertical O3 profiles below 5 km can be grouped into 5 categories: (1) peak mixing ratio type, (2) well-mixed type, (3) layered-structure type, (4) episodic pollution type and (5) altitudinal increasing type. Vertical distributions of O3 affected by regional transport of polluted air masses were investigated. Transport of polluted air from high latitudes of northern China, accompanying subsiding motion of air and stagnant atmospheric conditions are important factors that lead to high mixing ratios of O3 at Lin'an. The stagnant atmospheric conditions associated with a continental high pressure system and pollution plume transported from the YRD and central-eastern China also lead to regional accumulation of O3 and high O3 mixing ratio at Lin'an. Long-range transport of O3 and pollutants from the Pearl River Delta in South China and in-situ O3 formation also resulted in elevated O3 mixing ratios at around 1 km altitudes and layered O3 distribution in the lower troposphere.

  6. Analysis of Gao Jia-lin's life tragedy in Lu Yao's"life"%路遥《人生》中高加林人生悲剧的分析

    Institute of Scientific and Technical Information of China (English)

    杜刚秀

    2013-01-01

    Gao Jia-lin personality is very complex, is shape the classic literary by Lu Yao, but also the Chinese contemporary literature in the gallery of immortal images. Gao Jia-lin want to realize their own value, want to have a bright future and perfect love, and therefore exhibit an extraordinary entrepreneurial spirit, but ultimately failed to keep the faith and his principles, resulting in his pursuit of all ended in failure, his life is full of tragic color. A careful analysis of the novel, can be found the cause of Gao Jia-lin's life tragedy both factors of society, and his own personal factor.%高加林的性格十分复杂,是路遥塑造的经典的文学典型,同时也是中国当代文学画廊中不朽的文学形象。高加林想要实现自身的价值,想拥有美好的前程与完美的爱情,并且为此表现出非凡的进取精神,但是高加林最终没有能坚守自己的信念与原则,致使他的这些追求均以失败而告终,他的人生充满了悲剧色彩。认真分析小说,可以发现造成高加林人生悲剧的原因既有社会层面的因素,又有他个人的因素。

  7. Caenorhabditis elegans lin-35/Rb, efl-1/E2F and other synthetic multivulva genes negatively regulate the anaphase-promoting complex gene mat-3/APC8.

    Science.gov (United States)

    Garbe, David; Doto, Jeffrey B; Sundaram, Meera V

    2004-06-01

    Retinoblastoma (Rb)/E2F complexes repress expression of many genes important for G(1)-to-S transition, but also appear to regulate gene expression at other stages of the cell cycle. In C. elegans, lin-35/Rb and other synthetic Multivulva (SynMuv) group B genes function redundantly with other sets of genes to regulate G(1)/S progression, vulval and pharyngeal differentiation, and other unknown processes required for viability. Here we show that lin-35/Rb, efl-1/E2F, and other SynMuv B genes negatively regulate a component of the anaphase-promoting complex or cyclosome (APC/C). The APC/C is a multisubunit complex that promotes metaphase-to-anaphase progression and G(1) arrest by targeting different substrates for ubiquitination and proteasome-mediated destruction. The C. elegans APC/C gene mat-3/APC8 has been defined by temperature-sensitive embryonic lethal alleles that strongly affect germline meiosis and mitosis but only weakly affect somatic development. We describe severe nonconditional mat-3 alleles and a hypomorphic viable allele (ku233), all of which affect postembryonic cell divisions including those of the vulval lineage. The ku233 lesion is located outside of the mat-3 coding region and reduces mat-3 mRNA expression. Loss-of-function alleles of lin-35/Rb and other SynMuv B genes suppress mat-3(ku233) defects by restoring mat-3 mRNA to wild-type levels. Therefore, Rb/E2F complexes appear to repress mat-3 expression.

  8. BASES PARA LA ZONIFICACIÓN AGROECOLÓGICA EN EL CULTIVO DEL CACAO (Theobroma cacao, Lin) POR MEDIO DEL CRITERIO DE EXPERTOS

    OpenAIRE

    Giclis M. Suárez; René Florido Bacallao; Francisco Soto Carreño; Alberto Caballero Núñez

    2013-01-01

    El objetivo del presente trabajo fue establecer las bases para la zonificación agroecológica del cacao (Theobroma cacao, Lin) por medio del criterio de expertos mediante el método Delphi. Se seleccionaron expertos de diferentes esferas y se determinó el nivel de experticia y el nivel de competencia de cada experto respecto a la problemática relacionada con la definición de los factores que definen la ubicación del cultivo. Para ello se elaboró y aplicó un sistema de rondas de preguntas o cues...

  9. 林咸明教授治疗颈源性头痛经验%Professor Lin Xianming's Experience on Treatment of Cervical Headache

    Institute of Scientific and Technical Information of China (English)

    陈丽平; 李金霞

    2012-01-01

    [Objective]To summarize the clinical experience on treating cervical source headache by using warming acupuncture.[MethodjTo collect and analyze the theory and methodology of Pro. Lin Xianming's clinical treatment on cervical source headache. [Result] Professor Lin applys the theory of anatomy and muscle along meridians in his diagnosis and treatment on cervical source headache,which is based on its origin theory of "nerve entrapment doctrine" and "aseptic inflammation". His acupuncture prescription is characterized by selecting acupoints of the corresponding meridians,especially the acu-points and ahshi-points located at occipitonuchal and upper thoracic palpation.Professor Lin pays more attention to the combination of warming acupuncture and medicine to promote the blood circulation and to dredge collaterals to stop pain, [conclusion] Professor Lin has great innovation on treatment of cervical source headache and the combination of warming acupuncture with medicine treatment on cervical headache has significant effect in clinic.%[目的]总结林咸明教授温针灸治疗颈源性头痛的临床经验.[方法]对林咸明教授临床治疗颈源性头痛的理论及方法进行整理与分析.[结果]林咸明教授治疗颈源性头痛基于“神经卡压”与“无菌性炎症”成因说,在诊断及治疗上结合解剖学理论与经筋学说,着重枕项及胸椎上部触诊同时确定阿是穴并结合循经及远道取穴组方,重用温针灸结合药物以活血通络止痛.[结论]林咸明教授治疗颈源性头痛理论有较大创新,其温针灸结合通络药治疗颈源性头痛效果显著.

  10. A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.

    Science.gov (United States)

    Joshi, Shaurya; Wei, Jianqin; Bishopric, Nanette H

    2016-02-01

    The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. GENII-LIN-2.1: an open source software system for calculating radiation dose and risk from radionuclides released to the environment.

    Science.gov (United States)

    Teodori, Francesco; Sumini, Marco

    2008-12-01

    GENII-LIN is an open source radiation protection environmental software system running on the Linux operating system. It has capabilities for calculating radiation dose and risk to individuals or populations from radionuclides released to the environment and from pre-existing environmental contamination. It can handle exposure pathways that include ingestion, inhalation and direct exposure to air, water and soil. The package is available for free and is completely open source, i.e., transparent to the users, who have full access to the source code of the software.

  12. Contribución al conocimiento de la Epizootiología y Biología del Cathartes aura Lin (Contribution to the knowledge of the Epizootiology and Biology of the Cathartes aura Lin.

    Directory of Open Access Journals (Sweden)

    Isacc J. Rotella

    2006-01-01

    Full Text Available Con el objetivo de esclarecer el papel epizoodémico del Catharthes aura Lin. (aura y el fundamento de su resistencia frente a los microorganismos y toxinas que ingiere, se realizó una investigación en 53 ejemplares, que comprendió la infección artificial de 12 animales con B. abortus, M. bovis, S. aureus y S. typhimurium y, en animales no inoculados, bacteriología, parasitología, serología (brucelosis y leptospirosis, electroforesis del suero, hematología y medición del pH de órganos del tracto digestivo. En las auras infectadas por vía oral solamente se recuperó el microorganismo en una en que se aisló M. bovis de un exudado bucal; por vía intramuscular, un animal infectado con S. aureus presentó lesiones en el punto de inoculación y otro con S. typhimurium, alteraciones macroscópicas compatibles con salmonelosis. La bacteriología general fue negativa en el 72,5% de los animales siendo el germen mas frecuentemente aislado E. coli b hemolítica (12,5%. Las pruebas serológicas fueron negativas. En los proventrículos se encontraron parásitos parecidos a los tetrámeros de las aves (7,5% y en los intestinos ooquistes de Coccidia sp. (19,4%. No se detectaron hemoparásitos en sangre ni ectoparásitos en las plumas. Según la electroforesis del suero, las fracciones alfa 1 y beta no se delimitaron nítidamente y corrieron muy unidas a la albúmina la primera y a la gamma la segunda. El pH del aparato digestivo resultó más ácido a medida que el muestreo se alejó del pico, presentando el mayor grado de acidez el estómago muscular rudimentario (2,9. El aura posee un formidable poder destructivo de los microorganismos que ingiere por lo que no representa un gran peligro epizoodémico, por el contrario, contribuye a eliminar desperdicios que pueden ser focos de enfermedades. Al parecer su resistencia es independiente de la constitución globulínica del suero y la acidez del estómago muscular rudimentario constituye su

  13. A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation.

    Science.gov (United States)

    Li, Meng Amy; Amaral, Paulo P; Cheung, Priscilla; Bergmann, Jan H; Kinoshita, Masaki; Kalkan, Tüzer; Ralser, Meryem; Robson, Sam; Meyenn, Ferdinand von; Paramor, Maike; Yang, Fengtang; Chen, Caifu; Nichols, Jennifer; Spector, David L; Kouzarides, Tony; He, Lin; Smith, Austin

    2017-08-18

    Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naïve pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naïve pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations.

  14. Expression of TAT recombinant Oct4, Sox2, Lin28, and Nanog proteins from baculovirus-infected Sf9 insect cells.

    Science.gov (United States)

    Pan, Chuanying; Jia, Wenchao; Lu, Baisong; Bishop, Colin E

    2015-02-10

    Somatic cell reprogramming has generated enormous interest, following the first report of generation of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, but the integration of viral transgenes into the genome is unlikely to be accepted. Given these safety considerations, a method for virus-free transient gene expression from suspension-adapted Sf9 insect cells was developed. Here, we expressed transactivator of transcription (TAT)-fused proteins, Sox2, Oct4, Lin28, and Nanog in Sf9 cells using the baculovirus expression vector system (BEVS). The molecular weights of the TAT-Sox2, TAT-Oct4, TAT-Lin28, and TAT-Nanog fusion proteins were 36kD, 40kD, 24kD, and 36kD, respectively. Further investigation indicated that most of the recombinant proteins remained in the nuclei of the Sf9 insect cells and were therefore unavailable for purification and cellular reprogramming. Once this problem has been solved, it seems likely that protein expressed from baculovirus-infected Sf9 insect cells will be the method of choice for cellular reprogramming.

  15. Analysis of Lin Yutang' s Female Psychological Worship%林语堂女性崇拜心理探析综述

    Institute of Scientific and Technical Information of China (English)

    石秋仙

    2012-01-01

    This article focuses on the analysis of Lin Yutang' s female psychological worship through five fac- tors, including the influence of famous prostitute, the psychological compensation from the romantic love, the influ- ence of marriage and relatives, the influence of traditional Chinese culture ( Lin Yutang is affected by the images of Taoist motherhood worship and women in Dream of the Red Chamber) , the influence of studying and living abroad. All of them were embodied by his female characters he shaped in his novels.%林语堂的女性崇拜心理的探析主要有五个方面:名妓情结的影响,浪漫爱情的补偿心理的影响,婚姻及亲人的影响,中国传统文化硝影响(名著《红楼梦》中的女性形象的影响以及道教母性崇拜对林语堂的影响),西方留学定居生活的影响。这些因素的影响都体现在了林语堂小说的女性人物形象塑造上。

  16. My Viewpoint on the Research of Lin Shu and His Paraphrase%林纾及其"译述"研究之我见

    Institute of Scientific and Technical Information of China (English)

    秦莉莉

    2015-01-01

    林纾是清末民初著名国学大师与翻译家.他以深厚的国学功底与流畅生动的语言,创造了特有的译文风格,对中国文学翻译做出了巨大贡献. 林纾与人合译的独特方式被称为"译述". 他是备受争议的带有传奇色彩的人物,译述的百多部优秀作品影响很大,而思想的矛盾又让他不能融入时代大潮.%Lin Shu was a famous master of sinology and translator in the late Qing Dynasty and the early Republic of China. He created a unique style of translation and made a great contribution to the translation of Chinese literary translation. A unique way co-translated by Lin Shu and others was called "paraphrase." He was a controversial legendary figure and more than 100 outstanding paraphrased works influenced greatly while his contradictory thoughts kept him from fitting in the tide of the times.

  17. Lin Shu's Translation of Shakespeare's Plays from Perspective of Skopos Theory%目的论视角下的林纾莎剧翻译

    Institute of Scientific and Technical Information of China (English)

    何冀; 王治江

    2015-01-01

    林纾一生不仅翻译了大量的西方文学作品,在莎士比亚戏剧翻译方面也做出了重要贡献,是我国正式署名出版莎剧翻译作品的第一人,对中国早期戏剧的发展起到了推动作用。林译莎剧有其显著特点,从目的论的视角进行分析研究,有助于深入理解林纾的莎剧翻译实践。%Lin Shu not only translated a large number of Western literary works ,but also made great contri‐bution to the translation of Shakespeare's plays in China .He was the first Shakespeare's plays translator who put his signature on the published work .His translation of Tales From Shakespeare greatly fostered the development of Chinese drama in early years .From a perspective of Skopos T heory ,a deeper under‐standing of Lin Shu's translation of Shakespeare's plays was provided .

  18. AKTIVITAS KITINASE, LESITINASE, DAN HEMOLISIN ISOLAT DARI BAKTERI IKAN NILA (Oreochromis niloticus Lin. YANG DIKULTUR DALAM KERAMBA JARING APUNG WADUK JATILUHUR, PURWAKARTA

    Directory of Open Access Journals (Sweden)

    Wibowo Mangunwardoyo

    2016-11-01

    Full Text Available Aeromonas hydrophila Lin. merupakan bakteri patogen oportunistik akuatik yang virulensinya dipengaruhi oleh adanya enzim kitinase, lesitinase, dan toksin haemolisin, merupakan penyebab kematian ikan nila yang tinggi. Penelitian bertujuan untuk mengamati aktivitas enzim kitinase, lesitinase, dan toksin hemolisin dari 30 ikan nila dari keramba jaring apung waduk Jatiluhur dengan metode tehnik agar. A. hydrophila menunjukkan positif virulen ditunjukkan adanya zona bening untuk lesitinase sebesar 7,9 mm; kitinase 8,0 mm; dan hemolisin 6,6 mm dibandingkan dengan isolat Enterobacter sp., Pseudomonas sp., dan Vibrio sp. Hal ini menunjukkan bahwa A. hydrophila bersifat patogen dan virulen terhadap ikan nila. Aeromonas hydrophila Lin. is one of opportunistic aquatic pathogen bacteria where its pathogenic behavior is influenced by chitinase, lechitinase, and toxin haemolycine, and causes high mortality in nile tilapia culture. The purpose of the research was to observe the activities of two A. hydrophila’s enzymes i.e.: chitinase and lechitinase, and one extracelullar toxin, haemolycine, isolated from 30 nile tilapias cultured in floating net cage at Jatiluhur using quantitative plate assay technique. A. hydrophila was positive virulent marked with transparent zone of lechitinase of 7.9 mm, haemolycin of 6.6 mm, and chitinase of 8.0 mm compared to Enterobacter sp., Pseudomonas sp., and Vibrio sp. Therefore, A. hydrophila is determined as highly pathogenic bacterium and virulent for nile tilapia.

  19. The establishment and evaluation of SHA.LIN nephrolithometry scoring system for predicting the stone-free rate of percutaneous nephrolithotomy%SHA.LIN 评分系统的建立及其在预测经皮肾镜取石术结石清除率中的价值

    Institute of Scientific and Technical Information of China (English)

    彭国辉; 李汉忠; 张玉石; 张学斌; 李秉诚; 曹满超; 冯元法; 董德鑫; 肖河

    2015-01-01

    Objective To propose SHA.LIN nephrolithometry scoring system for assessing and predicting the stone-free rate of percutaneous nephrolithotomy ( PCNL) and to investigate the clinical value of SHA.LIN scoring system for nephrolithiasis in patients undergoing PCNL .Methods A literature review from 1976 to 2014 was performed to identify clinically relevant and reproducible variables that could affect the outcomes of PCNL. Six reproducible variables available from preoperative noncontrast-enhanced computed tomography were measured , including stone size ( S) , hydronephrosis ( H) , anatomic distribution (A), length of tract(L), indicator of CT(I), number of involved calices(N) and was named as SHA.LIN nephrolithometry scoring system .A retrospective analysis was conducted of clinical data of 116 patients with nephrolithiasis undergoing PCNL from June 2011 to March 2015. The general conditions , preoperative information , stone characteristics and perioperative variables were collected . The correlation of nephrolithometry scores based on SHA.LIN scoring system with stone-free status, operation time, blood loss, length of hospital stay and postoperative complications were analyzed . Receiver operating characteristic ( ROC) curves was drawn to detect sensitivity and specificity of SHA .LIN score in predicting the stone-free rates of PCNL.Results The SHA.LIN score was 9.13 ±2.24 in this cohort.The stone free rate was 75.9%(88/116).Postoperative complications occurred in 32 (27.6%) cases.In those patients with stone free, the SHA.LIN score was 8.27 ±1.62, significantly lower than that in those patients with residual stones 11.86 ±1.72 ( t =-10.069, P=0.000) .The SHA.LIN score showed significant correlation with the postoperative stone free status, operation time, estimated blood loss (P0.05).The area under curve of ROC curves for the SHA.LIN scoring system was 0.923 ( 95%CI 0.870 -0.975 ) . Conclusions The SHA.LIN nephrolithometry scoring system can predict postoperative

  20. 贺麟对康德哲学的认识和探索%He Lin's Understanding and Exploration on Kant's Philosophy

    Institute of Scientific and Technical Information of China (English)

    周良发

    2015-01-01

    As the authoritative expert on Hegel,He Lin had a lifelong interest in Hegel's research and transla-tion of philosophy,but he also cast the academic vision to Kant and his philosophy. Its reason can be roughly nor-malized as three factors such as the inner logic of the development of German classic philosophy,the match of Kant's moral philosophy and Chinese Confucianism,and the similar social situation in modern China and the Germany in the era of Kant. Based on the academic idea of Chinese and Western master,He Lin made a deep study on philoso-phy translation theory of Kant and title translation of his works,he carefully ran through the spread of Kant's philos-ophy in China and modern scholars'study on Kant. He Lin's concern and translation on Kant and his philosophy undoubtedly has a positive guiding role that the younger Neo-Confucian used Kant's philosophy to interpret the mo-dernity of Confucianism.%作为权威的黑格尔研究专家,贺麟毕生钟情于黑格尔哲学的研究和翻译,但他同时将学术视野投向康德及其哲学。其缘由大体可归为德国古典哲学演进的内在理路、康德的道德哲学与中国儒家思想若合符节及现代中国与康德时代之德国的社会情境相似等三种因素。基于“中西会通”的学术理念,贺麟对哲学翻译理论、康德著作译名作了深度探讨,对康德哲学在中国的传播及近现代学人的康德研究予以细密爬梳。贺麟对康德及其哲学的关注与译介,对后辈新儒家运用康德哲学来阐释儒家思想的现代性无疑具有积极的导向作用。

  1. Design of Software and Hardware of Automotive Lighting Systems Based on LIN Bus%基于LIN总线的汽车照明系统软硬件开发

    Institute of Scientific and Technical Information of China (English)

    陈恩策; 黄莹; 唐厚君

    2013-01-01

    LIN总线作为汽车电子中常见的一种总线协议,因其通用性广、成本低廉受到众厂商的青睐.为了将LIN总线应用到汽车照明系统上,对LIN报文帧进行了详细的研究,对各个字节的内容进行详细的解释.随后在通用串口的基础上,设计了一套基于LIN总线的汽车照明系统,并给出了主从节点不同的硬件电路图和软件流程图.最终完成了整个照明系统的开发要求.%LIN bus,as a bus protocol commonly used in automotive electronics,is favored by most manufacturers,because of its wide versatility and low cost.In order to apply LIN bus to automotive lighting system,this paper studies in detail the LIN message frame,and gives an elaborately explanation of the contents of each byte.On the basis of the general-purpose serial port,the paper introduces a design of a set of automotive lighting systems based on the LIN bus,and gives the master and slave nodes of different hardware schematics and software flow chart.

  2. Efeito e modo de ação das bacteriocinas produzidas por Lactococcus lactis subsp. lactis ITAL 383, ATCC 11454 e CNRZ 150 contra Listeria innocua LIN 11 Effect and mode of action of the bacterioncin produced by Lactococcus. lactis subsp. lactis ITAL 383, ATCC 11454 e CNRZ 150 against Listeria innocua LIN 11

    Directory of Open Access Journals (Sweden)

    Izildinha MORENO

    1999-01-01

    Full Text Available O efeito e o modo de ação das bacteriocinas produzidas por L. lactis subsp. lactis ITAL 383 e CNRZ 150 são similares à nisina de L. lactis subsp. lactis ATCC 11454. Estas bacteriocinas apresentaram um modo de ação bactericida, causando a lise de células de L. innocua LIN 11, associada ao decréscimo da absorbância e da viabilidade celular. O efeito letal foi maior para células em fase exponencial comparativamente à fase estacionária de crescimento. A adsorção dessas bacteriocinas às células de L. innocua LIN 11 foi muito rápida e influenciada pelo pH do meio de suspensão; adsorção máxima foi verificada a pH 6,0 e logo após o contato inicial. Perda completa de adsorção ocorreu em pH 2,0.The effect and mode of action of the bacteriocin produced by L. lactis subsp. lactis ITAL 383 and CNRZ 150 are similar to the nisin produced by L. lactis subsp. lactis ATCC 11454. It was clearly bactericidal, and caused lysis of a strain of L. innocua LIN 11 detected by the decrease of absorbance values and the cell viability. Their lethal effect was considerably higher during the logarithmic growth when compared to the stationary phase. Adsorption developed rapidly and was influenced by the pH value of the suspension medium. Maximum adsorption was observed at pH 6,0 and immediately after initial contact and loss at pH 2,0.

  3. LIN28A, a sensitive immunohistochemical marker for Embryonal Tumor with Multilayered Rosettes (ETMR), is also positive in a subset of Atypical Teratoid/Rhabdoid Tumor (AT/RT).

    Science.gov (United States)

    Rao, Shilpa; Rajeswarie, R T; Chickabasaviah Yasha, T; Nandeesh, Bevinahalli N; Arivazhagan, Arimappamagan; Santosh, Vani

    2017-07-25

    CNS embryonal tumors comprise a group of highly malignant neoplasms with a wide spectrum of histomorphological entities that includes Medulloblastoma (MB), Atypical Teratoid/Rhabdoid Tumor (AT/RT), Neuroblastoma (NB), Ganglioneuroblastoma (GNB), Embryonal Tumor with Multilayered Rosettes (ETMR), and the embryonal tumor-Not Otherwise Specified (NOS). The entity ETMR includes previously described histopathologic patterns-Embryonal Tumor with Abundant Neuropil and True Rosettes (ETANTR), Ependymoblastoma (EBL), and Medulloepithelioma (MEPL). Based on the histopathological similarities (multilayered rosettes) among ETANTR, EBL, and MEPL, as well as uniform clinical behavior and common molecular genetic characteristics, the WHO revision has created a new entity, "ETMR." Immunoreactivity of LIN28A has been identified as a sensitive tool for the diagnosis of this entity. Since there is a paucity of literature regarding immunoreactivity of LIN28A across all embryonal CNS tumors, the present study was undertaken. During the 5-year study period (2012 to 2016), all the embryonal tumors (MB, AT/RT, other embryonal tumors-ETANTR, MEPL, PNET) that had been earlier diagnosed in the department of neuropathology (cases operated in our institute as well as received as referral) were reviewed. The archived Hematoxylin and Eosin (H&E) and the available immunohistochemistry (IHC) sections were studied. Further, for the other embryonal tumors where the paraffin blocks were available, an extended panel of IHC was performed for confirming the diagnosis of embryonal tumor and only confirmed cases were included in the study. The demographic details of the study cohort were noted. IHC for LIN28A was performed on conventional sections. A total of 396 cases of embryonal tumors including 302 MB, 72 AT/RT, and 22 other embryonal tumors were diagnosed during the study period. Among these, 80 MB, 35 AT/RT, 4 ETANTR, 1 MEPL, 4 NB, 2 GNB, and 1 CNS embryonal tumor-NOS (total-127) were included for

  4. Stabilit\\'e orbitale pour le syst\\`eme de Vlasov-Poisson gravitationnel, d'apr\\`es Lemou-M\\'ehats-Rapha\\"el, Guo, Lin, Rein et al. [Orbital stability for the gravitational Vlasov-Poisson system, after Lemou-M\\'ehats-Rapha\\"el, Guo, Lin, Rein et al.

    CERN Document Server

    Mouhot, Clément

    2012-01-01

    This paper reviews the recent mathematical progresses made on the study of the orbital stability properties for the gravitational Vlasov-Poisson system. We present in details the paper of Lemou, M\\'ehats and Rapha\\"el (Inventiones 2011) and we review also the previous works by Dolbeault, Guo, Hadzic, Lin, Rein, S\\'anchez, Soler, Wan, Wolansky. We also include a discussion of the history of this topic and the pioneering works by physicists like Antonov, Lynden-Bell and Aly. This is the text of a Bourbaki seminar given in november 2011 (in french).

  5. Réduction des approvisionnements pétroliers multiples dans les programmes linéaires de raffinage Reduction of Multiple Oil Supplies in Linear Refining Programs

    Directory of Open Access Journals (Sweden)

    Bond J.

    2006-11-01

    Full Text Available L'article propose une méthode pour réduire le nombre des pétroles bruts nécessaires pour représenter un approvisionnement lors de l'utilisation de programmes linéaires de raffinage, ceci afin de diminuer la taille et les temps de calcul de ces modèles. Les techniques utilisées sont celles de l'analyse de données multidimensionnelles. Un exemple est traité pour illustrer la méthode. The article proposes a method for reducing the number of crude ails needed to make up the supply in linear programs of refining, in order ta cut clown on the size and calculation time of such models. The method uses techniques of multidimensional data analysis. An exemple is considered in order to illustrate the method.

  6. Modélisation et commande non linéaire en couple d'une machine à réluctance variable à double saillance

    Science.gov (United States)

    Cailleux, H.; Le Pioufle, B.; Multon, B.

    1996-01-01

    The research of a control to reduce the torque ripple of a Switched Reluctance Machine (SRM) is the main aim in this paper. The SRM is very attractive because of its simple structure. Unfortunately, its polyphase torque is naturally pulsed because of the highly nonlinear electromagnetic characteristics and because the phases have to be successively commutated in order to maintain a continuous rotation. First, the electromagnetic characteristics (torque and flux with regard to the position and the current) have to be very precisely determined. Several experimental methods of characterization are presented. A model based on this experimental electromagnetic characterization is necessary for the synthesis of the control. The models found in the literature, compared with the experimental data, are not adapted to the SRM under study. An original model is then proposed. After defining an appropriate strategy for the phase commutation, the limits of the classical linear control (Proportional Integral controller) are determined. In order to compensate the SRM nonlinearities, a nonlinear torque control has been simulated and tested. Very promising results have been obtained at low and medium speeds. Dans cet article, une commande est recherchée afin de réduire les ondulations de couple d'une Machine à Réluctance Variable à Double Saillance (MRVDS). La structure très simple de la MRVDS la rend très attractive. Malheureusement, son couple polyphasé est naturellement pulsé du fait des caractéristiques électromagnétiques fortement non linéaires et de la nécessité de commuter successivement les phases pour assurer une rotation continue. Dans un premier temps, il est indispensable de déterminer très précisément les caractéristiques électromagnétiques (couple et flux en fonction de la position et du courant). Plusieurs méthodes expérimentales de caractérisation sont présentées. Un modèle s'appuyant sur cette caractérisation électromagnétique exp

  7. Mise en pratique de LSPI pour la commande linéaire quadratique adaptative d'une surface de manipulation à coussin d'air actif.

    OpenAIRE

    2010-01-01

    National audience; Cet article présente l'application de l'algorithme LSPI de Lagoudakis & Parr (2003) à la commande d'un système linéaire avec coût quadratique selon le protocole initialement proposé par Bradtke (1993). Le dispositif contrôlé est une surface active capable de mouvoir un objet sur un coussin d'air et dont la dynamique varie fortement en fonction de l'objet utilisé. La méthode d'apprentissage est validée en simulation avant d'être appliquée au système réel. Les résultats expér...

  8. Stabilité linéaire d'un écoulement présentant une onde de choc

    OpenAIRE

    ROBINET, Jean-Christophe

    1999-01-01

    Cette thèse est consacrée à l'étude de la stabilité linéaire des ondes de choc en écoulement transsonique et supersonique. Dans un certain nombre de situations concrètes, en particulier en présence de décollement, les ondes de choc ne sont pas stationnaires ; elles génèrent des phénomènes instationnaires à des fréquences relativement basses susceptibles d'engendrer des vibrations de la structure des avions (phénomène du tremblement) ou dans des moteurs fusées (problème de charges latérales). ...

  9. Quando "falha a fala" e "fala a bala": lingua(gem e violência em Cidade de Deus, de Paulo Lins

    Directory of Open Access Journals (Sweden)

    Rita Gabrielli Pereira

    2014-08-01

    Full Text Available Cidade de Deus traz em si a história da construção do conjunto habitacional, cujo nome intitula o romance, e de sua transformação em uma das favelas mais violentas do Rio de Janeiro, por meio do entrecruzamento das histórias de Cabeleira, Bené, Zé Pequeno e Busca-Pé. Concebendo o romance, nos atos da escrita e da leitura, como uma enunciação (BENVENISTE, 1989a; 1989b; 1995a; 1995b entre autor e leitor, constituída por outras enunciações — entre narrador e narratário e entre personagens — a partir do "ato ficcional" (ISER, 2002 do autor, vamos nos guiar por essa tessitura de/entre histórias para rastrear o modo como Lins relaciona linguagem e violência.

  10. 293FT cells transduced with four transcription factors (OCT4, SOX2, NANOG, and LIN28 generate aberrant ES-like cells

    Directory of Open Access Journals (Sweden)

    Kobayashi H

    2010-01-01

    Full Text Available The HEK 293 cell line (293 cells was derived from human embryonic kidney (HEK cells grown in tissue culture. 293 cells are very easy to grow and transfect and have been widely used in cell biological research for many years. 293 cells have many of the properties of immature neurons, suggesting that they represent a transformed neuronal cell present in the original kidney culture, and they are not useful as an in vitro model for kidney cell function. The 293T cell line contains the SV40 large T-antigen, which allows the episomal replication of transfected plasmids containing the SV40 origin of replication, and 293FT cells are a fast-growing variant. A recent report showed that introducing a set of transcription factors associated with pluripotency into human somatic cells can directly reprogram them to produce induced pluripotent stem (iPS cells. To date, however, iPS cells have not been generated from immortalized cells. We examined whether iPS cells could be generated from 293 FT cells transfected with four transcription factors (OCT4, SOX2, NANOG, and LIN28. The obtained cells morphologically resembled human ES cells, and showed a similar marker gene expression pattern. These cells had an impaired ability to differentiate, and formed immature ectodermal tumors after they were transplanted into nude mice. Thus, we could not derive fully reprogrammed iPS cells from 293FT cells. We conclude that the 293FT cells transduced with OCT4, SOX2, NANOG, and LIN28 produced aberrant ES-like cells.

  11. 生态女性主义视角下的林黛玉形象%An Eco-feminism Analysis of the Image of Lin Daiyu

    Institute of Scientific and Technical Information of China (English)

    王军霞; 杜伟; 董红芸

    2011-01-01

    林黛玉是中国文学史上最深入人心、最富有艺术力量的女性形象,她有花之容貌,竹之气节,散发着一种诗意美和自然美。在封建思想和男权主义的笼罩下,她对自然的纯真热爱和对爱情的炽热追求具有前卫性和启蒙性,她的爱情悲剧命运,激发着人们的思考,呼唤着女性的觉醒,处处渗透了生态女性主义的思想。20世纪90年代兴起的生态女性主义是一种引人瞩目的文学理论流派,此理论将生态批评与女性主义批评相结合,提倡正确处理人和自然的关系、男人和女人的关系,为林黛玉悲剧形象的解读提供了一个更深入更全面的新视觉。%Lin Daiyu is the most charming character that moves people deeply.She is elegant,noble and rebellious.Although she lived in the male-dominated feudal society,she was quite distinguished and had a deep love for nature and Jia Baoyu.Her tragedy was thought-provoking and raised the feminism awareness.The rising of eco-feminism in the 1990s offers a new perspective in the analysis of Lin Daiyu.The theory eco-feminism combines nature and female together,proposing a new way in dealing with the relationship between nature and human,man and woman.

  12. Lin Daiyu's Death Awareness in A Dream of Red Mansions%论《红楼梦》中林黛玉的死亡意识

    Institute of Scientific and Technical Information of China (English)

    唐永泽

    2012-01-01

    Lin Daiyu's orphaned childhood resulted in a deep imprint of death awareness in her inner world. Because of homelessness and loneliness resulted from her dependence on others, she likes solitude and hates living in groups, and she often weeps and mentions "death" in her daily life. Her poetry and song prose voice her inner temperament: plaintive sadness, uneven depression, decadent repression, and noble haught- iness,meanwhile they express a strong hunch of her fate of life and death, containing a strong sense of death. Death awareness endows Lin Daiyu with the most poetic and poignant life, and makes A Dream of Red Mansions become an elegy of life of women and an enduring unprecedented tragedy.%林黛玉自幼父母双亡,寄人篱下的飘零与孤独,使她喜散不喜聚,在日常生活中爱哭流泪,经常说“死”。林黛玉诗词抒写其内心的哀伤凄怆、抑郁不平、苦闷颓伤的情感,孤傲高洁的性情,对自己生离死别的命运有强烈的预感,蕴含着强烈的死亡意识。死亡意识使林黛玉成为最富有诗意也最凄美的生命,使《红楼梦》成为一曲女性生命的挽歌,一出旷世未有的悲剧。

  13. The Story of Heathcliff’s Journey Back to Wuthering Heights de Lin Haire-Sargeant (1992, ou le « deux en un » de la ré-écriture The Story of Heathcliff’s Journey Back to Wuthering Heights by Lin Haire-Sargeant (1992, and a “Two in one” Rewrite

    Directory of Open Access Journals (Sweden)

    Isabelle Roblin

    2009-10-01

    Full Text Available Lin Haire-Sargeant’s 1992 novel The Story of Heathcliff’s Journey Back to Wuthering Heights is typical of the interest shown by contemporary American writers in Victorian novels. It could indeed be classified doubly as a “retro-Victorian novel” since it partly re-writes not only Emily Brontë’s most famous novel, Wuthering Heights, as the title points out, but also, somewhat less obviously, Charlotte Brontë’s Jane Eyre. We will study in this article how Lin Haire-Sargeant’s attempt at re-writing highlights the usual aims of the retro-Victorian novel: taking advantage of the blanks left by the source novels to propose to the reader a modern critical approach, while at the same time being as faithful as possible to the writing conventions of the 19th century, and suggesting another point of view on a well-known story, through a postmodern mixing of historical and fictive characters.

  14. On the Documentary Literature Creation of Lin Yutang Discussion on the Status of Lin Yutang in Literary History%论林语堂的纪实文学创作兼谈林语堂的文学史地位问题∗

    Institute of Scientific and Technical Information of China (English)

    章罗生; 刘鑫

    2015-01-01

    人们之所以在对林语堂的评价上产生分歧,林语堂之所以在文学史上无地位,首先是观念问题,其次是评价标准与学术视野问题。实际上,林语堂是继梁启超之后,致力于融汇中西文化,将中国传记文学推向现代化的标志性人物,在中国传记文学史上起了继往开来、承前启后的重要作用;他不仅开了以散文形式向西方传播中国文化的先路,而且也开了现代长篇纪实散文创作的先声。因此,单就纪实文学创作而言,林语堂就为中国文学作出了杰出贡献,在文学史上具有无可替代的重要地位。而如果联系小说等虚构文学创作,我们则更须重新评价林语堂的历史地位与文学成就。“林语堂现象”启示我们:在现当代文学史“重写”中,除了要更新以虚构为中心的传统观念与拓展海外华文文学的学科领域外,还须进一步解放思想,确立科学的史识、史观与评价标准。%The reason why people divide over the evaluation of Lin Yutang,and the absence of his posi-tion in the literary history appears to be the problem of conception,and the evaluation criteria as well as the academic vision.In fact,Lin Yutang was such an iconic figure who had been committed to the blending of Chinese and Western culture,and the modernization of Chinese biographical literature after Liang Qichao,which connected the past and future development of Chinese literature.He was not only such a pi-oneer who spread Chinese culture in the form of prose,but also an originator of modern long documentary prose.Therefore,in terms of documentary literature,Lin Yutang is such an outstanding contributor who possesses irreplaceable place in literary history.Moreover,taking fiction literature into consideration,we seriously need to reevaluate Lin's historical status and his literary achievements."Lin Yutang Phenome-non"shows that when rewriting modern and contemporary

  15. Periscopic Spine Surgery

    Science.gov (United States)

    2008-06-01

    Supplement 1, November 2007, 21-33, DOI 10.1007/s10278-007-9054-3. [Lin 2008] Ralph Lin; Peng Cheng; David Lindisch; Filip Banovac; Justin Lee...produce high muscular endurance [1]. Until the 1970s, free weights (e.g. barbells and dumbells) and Universal Gyms utilizing weight stacks driven by cable...significant disadvantage of inertial training. Although our goal was to simply emulate an inertial trainer, the oscillations could be reduced or even

  16. Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein.

    Directory of Open Access Journals (Sweden)

    Yangzom Doma Bhutia

    Full Text Available Overexpression of ribonucleotide reductase subunit M2 (RRM2, involved in deoxyribonucleotide synthesis, drives the chemoresistance of pancreatic cancer to nucleoside analogs (e.g., gemcitabine. While silencing RRM2 by synthetic means has shown promise in reducing chemoresistance, targeting endogenous molecules, especially microRNAs (miRNAs, to advance chemotherapeutic outcomes has been poorly explored. Based on computational predictions, we hypothesized that the let-7 tumor suppressor miRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in innately gemcitabine-resistant pancreatic cancer cell lines. Direct binding of let-7 miRNAs to the 3' UTR of RRM2 transcripts identified post-transcriptional regulation of RRM2 influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and chemosensitivity responses in a poorly differentiated pancreatic cancer cell line, MIA PaCa-2. Defective processing of let-7a precursors to mature forms, in part, explained the discrepancies observed with let-7a expressional outcomes. Consistently, the ratios of mature to precursor let-7a were progressively reduced in gemcitabine-sensitive L3.6pl and Capan-1 cell lines induced to acquire gemcitabine resistance. Besides known regulators of let-7 biogenesis (e.g., LIN-28, short hairpin RNA library screening identified several novel RNA binding proteins, including the SET oncoprotein, to differentially impact let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus -resistant pancreatic cancer cells. Further, LIN-28 and SET knockdown in the cells led to profound reductions in cellular proliferation and colony-formation capacities. Finally, defective processing of let-7a precursors with a positive correlation to RRM2 overexpression was

  17. miR-125b promotes early germ layer specification through Lin28/let-7d and preferential differentiation of mesoderm in human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Sharon S Y Wong

    Full Text Available Unlike other essential organs, the heart does not undergo tissue repair following injury. Human embryonic stem cells (hESCs grow indefinitely in culture while maintaining the ability to differentiate into many tissues of the body. As such, they provide a unique opportunity to explore the mechanisms that control human tissue development, as well as treat diseases characterized by tissue loss, including heart failure. MicroRNAs are small, non-coding RNAs that are known to play critical roles in the regulation of gene expression. We profiled the expression of microRNAs during hESC differentiation into myocardial precursors and cardiomyocytes (CMs, and determined clusters of human microRNAs that are specifically regulated during this process. We determined that miR-125b overexpression results in upregulation of the early cardiac transcription factors, GATA4 and Nkx2-5, and accelerated progression of hESC-derived myocardial precursors to an embryonic CM phenotype. We used an in silico approach to identify Lin28 as a target of miR-125b, and validated this interaction using miR-125b knockdown. Anti-miR-125b inhibitor experiments also showed that miR-125b controls the expression of miRNA let-7d, likely through the negative regulatory effects of Lin28 on let-7. We then determined that miR-125b overexpression inhibits the expression of Nanog and Oct4 and promotes the onset of Brachyury expression, suggesting that miR-125b controls the early events of human CM differentiation by inhibiting hESC pluripotency and promoting mesodermal differentiation. These studies identified miR-125b as an important regulator of hESC differentiation in general, and the development of hESC-derived mesoderm and cardiac muscle in particular. Manipulation of miR-125b-mediated pathways may provide a novel approach to directing the differentiation of hESC-derived CMs for cell therapy applications.

  18. 林风眠与艺术运动社的美育实践%Lin Fengmian and the Aesthetic Education Practice of the Art Movement Association

    Institute of Scientific and Technical Information of China (English)

    喻琴

    2016-01-01

    林风眠美育实践的明确宗旨和鲜明特色之一,便是通过立足于学校,大胆采用开门办学的方式,倡导艺术运动. 他在杭州组建国立艺术院后,便以该校教师为基本队伍,成立了"艺术运动社",积极投身于新艺术运动. 林风眠与艺专师生们将学校作为艺术运动的中心,除了在艺专校内经常举办各类规模不等的观摩和展览,发行艺术理论刊物之外,艺专的师生更是走出校外去办展,借以宣传艺术运动,扩大学校的影响,以期更好地促进美育的发展.%One of the clear aims and distinctive characteristics of Lin Fengmian,s aesthetic education practice is to use the school as a haven of art activities and, when necessary, go outside it to promote art.After the establishment of the National Art College in Hangzhou, he set up the"art movement association", of which the faculty of the college constituted the core, and actively engaged in the new art movement.Lin Fengmian, his colleagues and the students all regarded the college as the center of the art movement.In addition to hosting frequent exhibitions and exchanges of varying scales in the college and publishing art theory journals, teachers and students of the art college held exhibitions outside the college as well, so as to pro-mote the art movement, expand the influence of the art college and better advance the development of aesthetic education.

  19. Deneysel Diyabet Modelinde İntraperitoneal ve Subkutan İnsülin Uygulanmasının Peritoneal Solüt Geçirgenliği ve Ultrafiltrasyon Üzerine Etkileri

    OpenAIRE

    ÖZALP, Göksel; Ahmet IŞIK

    2014-01-01

    Giriş: Ultrafiltrasyon (UF) yetersizliği, periton diyalizi hastalarında en önemli diyaliz yetersizliği nedenlerinden birisidir. Diyabetik periton diyalizi hastalarında kan şekeri regülasyonu için intraperitoneal (İP) insülin uygulanabilmektedir. İnsülinin, TGF-β1 ve VEGF gibi büyüme faktörlerini artırarak fibroz gelişimi ve yeni damar oluşumlarına neden olduğu bilinmektedir. Çalışmamızda, deneysel diyabet modelinde, İP ve subkutan (SC) insülin uygulamalarının peritoneal membra...

  20. Matériaux : les nouveaux champs de recherche et développement pour la valorisation des fibres végétales techniques (lin fibres et chanvre)

    OpenAIRE

    Bono Pierre; Le Duc Anne; Lozachmeur Marie; Day Arnaud

    2015-01-01

    Les matériaux à base de fibres végétales techniques (lin et chanvre) sont une réalité depuis plusieurs années. Une étude récente de FranceAgriMer (Thonier et Bono, 2015) montre que leur développement est une réalité tout particulièrement dans le domaine du bâtiment (isolation, panneaux de particules, bétons), du transport (plasturgie, composite) et plus récemment des sports et loisirs et du luxe. Ces développements permettent de valoriser les propriétés différenciantes du lin fibre et du chan...

  1. 基于CAN/LIN总线的智能车身控制系统设计%Design of Intelligent Automotive Control System Based on CAN/LIN Bus

    Institute of Scientific and Technical Information of China (English)

    郭峰; 赵璇; 汪颖

    2011-01-01

    Aiming at many kinds of shortcomings existed in current automotive control system,a hybrid network control system based on CAN/LIN bus was designed. The MCP2551, MCP201 were used as CAN/LIN bus transceiver, respectively. MC9S12XDG128 as the gateway makes CAN/LIN network interactive communication possible. In addition,the combination switch module signals were transported via LIN bus to achieve the bus and modular of the automotive control system. Finally,taking the practical application demands of an ODM into account,low power consumption and system fault diagnosis were designed and the security of the system is high.%针对目前集中式车身控制系统的不足,设计了一种基于CAN/LIN总线混合网络的车身控制系统.将MCP2551、MCP201分别作为CAN/LIN总线的收发器,以MC9S12XDG128作为主控芯片实现网关控制功能,通过该网关实现CAN/LIN网络通信交互.另外对组合开关模块信号采用LIN总线传输,实现车身控制系统的总线化、模块化.并结合某主机厂实际应用需求,对系统进行低功耗和故障自诊断设计,构建了一套安全性较高的车身网络控制系统.

  2. RNA-binding protein L1TD1 interacts with LIN28 via RNA and is required for human embryonic stem cell self-renewal and cancer cell proliferation.

    Science.gov (United States)

    Närvä, Elisa; Rahkonen, Nelly; Emani, Maheswara Reddy; Lund, Riikka; Pursiheimo, Juha-Pekka; Nästi, Juuso; Autio, Reija; Rasool, Omid; Denessiouk, Konstantin; Lähdesmäki, Harri; Rao, Anjana; Lahesmaa, Riitta

    2012-03-01

    Human embryonic stem cells (hESC) have a unique capacity to self-renew and differentiate into all the cell types found in human body. Although the transcriptional regulators of pluripotency are well studied, the role of cytoplasmic regulators is still poorly characterized. Here, we report a new stem cell-specific RNA-binding protein L1TD1 (ECAT11, FLJ10884) required for hESC self-renewal and cancer cell proliferation. Depletion of L1TD1 results in immediate downregulation of OCT4 and NANOG. Furthermore, we demonstrate that OCT4, SOX2, and NANOG all bind to the promoter of L1TD1. Moreover, L1TD1 is highly expressed in seminomas, and depletion of L1TD1 in these cancer cells influences self-renewal and proliferation. We show that L1TD1 colocalizes and interacts with LIN28 via RNA and directly with RNA helicase A (RHA). LIN28 has been reported to regulate translation of OCT4 in complex with RHA. Thus, we hypothesize that L1TD1 is part of the L1TD1-RHA-LIN28 complex that could influence levels of OCT4. Our results strongly suggest that L1TD1 has an important role in the regulation of stemness.

  3. A Parallel and Concurrent Implementation of Lin-Kernighan Heuristic (LKH-2 for Solving Traveling Salesman Problem for Multi-Core Processors using SPC3 Programming Model

    Directory of Open Access Journals (Sweden)

    Muhammad Ali Ismail

    2011-08-01

    Full Text Available With the arrival of multi-cores, every processor has now built-in parallel computational power and that can be fully utilized only if the program in execution is written accordingly. This study is a part of an on-going research for designing of a new parallel programming model for multi-core processors. In this paper we have presented a combined parallel and concurrent implementation of Lin-Kernighan Heuristic (LKH-2 for Solving Travelling Salesman Problem (TSP using a newly developed parallel programming model, SPC3 PM, for general purpose multi-core processors. This implementation is found to be very simple, highly efficient, scalable and less time consuming in compare to the existing LKH-2 serial implementations in multi-core processing environment. We have tested our parallel implementation of LKH-2 with medium and large size TSP instances of TSBLIB. And for all these tests our proposed approach has shown much improved performance and scalability.

  4. DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest.

    Science.gov (United States)

    Baugh, L Ryan; Sternberg, Paul W

    2006-04-18

    Development is typically studied as a continuous process under laboratory conditions, but wild animals often develop in variable and stressful environments. C. elegans larvae hatch in a developmentally arrested state (L1 arrest) and initiate post-embryonic development only in the presence of food (E. coli in lab). In contrast to the well-studied dauer arrest, L1 arrest occurs without morphological modification, although larvae in L1 arrest are more resistant to environmental stress than developing larvae . Consistent with its role in dauer formation and aging, we show that insulin/insulin-like growth factor (IGF) signaling regulates L1 arrest. daf-2 insulin/IGF receptor mutants have a constitutive-L1-arrest phenotype when fed and extended survival of L1 arrest when starved. Conversely, daf-16/FOXO mutants have a defective-arrest phenotype, failing to arrest development and dying rapidly when starved. We show that DAF-16 is required for transcription of the cyclin-dependent kinase inhibitor cki-1 in stem cells in response to starvation, accounting for the failure of daf-16/FOXO mutants to arrest cell division during L1 arrest. Other developmental events such as cell migration, cell fusion, and expression of the microRNA lin-4, a temporal regulator of post-embryonic development, are also observed in starved daf-16/FOXO mutants. These results suggest that DAF-16/FOXO promotes developmental arrest via transcriptional regulation of numerous target genes that control various aspects of development.

  5. The RING finger/B-Box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegans

    Science.gov (United States)

    Hsieh, Jenny; Liu, Jing; Kostas, Stephen A.; Chang, Chieh; Sternberg, Paul W.; Fire, Andrew

    1999-01-01

    Context-dependent gene silencing is used by many organisms to stably modulate gene activity for large chromosomal regions. We have used tandem array transgenes as a model substrate in a screen for Caenorhabditis elegans mutants that affect context-dependent gene silencing in somatic tissues. This screen yielded multiple alleles of a previously uncharacterized gene, designated tam-1 (for tandem-array-modifier). Loss-of-function mutations in tam-1 led to a dramatic reduction in the activity of numerous highly repeated transgenes. These effects were apparently context dependent, as nonrepetitive transgenes retained activity in a tam-1 mutant background. In addition to the dramatic alterations in transgene activity, tam-1 mutants showed modest alterations in expression of a subset of endogenous cellular genes. These effects include genetic interactions that place tam-1 into a group called the class B synMuv genes (for a Synthetic Multivulva phenotype); this family plays a negative role in the regulation of RAS pathway activity in C. elegans. Loss-of-function mutants in other members of the class-B synMuv family, including lin-35, which encodes a protein similar to the tumor suppressor Rb, exhibit a hypersilencing in somatic transgenes similar to that of tam-1 mutants. Molecular analysis reveals that tam-1 encodes a broadly expressed nuclear protein with RING finger and B-box motifs. PMID:10580003

  6. 林译《黑奴吁天录》的修辞解读%A Rhetorical Interpretation of Lin Shu's T ranslation of Uncle Tom's Cabin

    Institute of Scientific and Technical Information of China (English)

    李艳玲

    2015-01-01

    T his paper applies the theory of rhetoric to an analysis of the Chinese translation of Uncle Tom's Cabin by Lin Shu .It interprets the manipulation of the material in the source text and the focus of the study is how the translator centered on target audience ,applying different rhetorical means to the translation to achieve his intention of the translation .%文章以西方修辞理论为参照,以个案研究的方法重新解读林译《黑奴吁天录》,重点分析译者在文本选择、话语建构及内容删改等方面,如何以受众为中心,诉诸各种修辞手段来处理原文本的内容,以圆满地实现自己的修辞意图。

  7. Remaining oil distribution in Ng33 bottom water reservoir of Lin 2-6 fault-block in Huimin depression and potential tapping in horizontal well

    Institute of Scientific and Technical Information of China (English)

    HAN Zuo-zhen; YANG Ren-chao; FAN Ai-ping; CHEN Qing-chun; SHAO Yun-tang

    2009-01-01

    Oil reservoirs with secondary bottom water in Ng33 members (in Guantao formation, Paleogene system) of Lin2-6 fault block in Huimin depression (Bohai Bay Basin) have entered the late stage of ultra-high water-containing-exploitation. Oil exploita-tion from vertical wells is becoming more and more inefficient. The reservoir type, with water displacing oil and the remaining oil distribution are specifically studied in order to improve the efficiency of the recovery ratio. An integrated scheme for adjusting horizontal wells has been designed and the key technique of the scheme optimized. The study shows that: 1) the positive rhythm of fluvial depositional features is the internal cause of the flooding of oil reservoirs while water injection, injection-production patterns and accumulative petroleum production are the external causes; 2) oil-water driving patterns have transferred from edge water ad-vancing to bottom-water-coning; distribution of the remaining oil mainly concentrates in the upper rhythm and top of the middle rhythm in Ng33 members; 3) a great deal of remaining oil is enriched in high positions of faults, in axes of tiny structures, in stagna-tion areas among water-injection wells and oil-wells and in tectonic saddle areas with sparse wells. Compared with vertical wells, horizontal wells have advantages such as high recovery, high off-take potential, high critical output, large controlling areas and long time of bottom-water breakthrough.

  8. 贺麟思辨精神与其哲学翻译%A Discussion on the Dialectical Thinking and Philosophy Translation of He Lin

    Institute of Scientific and Technical Information of China (English)

    郭勤

    2016-01-01

    贺麟是中国译介西方古典哲学著作的集大成者。其思辨精神发端于家庭的熏陶和国内的学习,发展于留学美国时期,成熟于留学德国时期。在哲学翻译实践中,贺麟专而不滥的选材特点、内化外学的文化立场以及止于至善的翻译态度,均展现出思辨精神。%He Lin was an outstanding translator for his achievements in translating western classical philosophy. At the threshold, he ac-quired the ability of dialectical thinking from his family education and study in homeland. Further study in America and Germany facilita-ted the ability. His exclusive choice of source works, introduction of exotic cultures to enrich his own, and industrious working on ver-sions for satisfactory sake, all bring the ability into full play.

  9. Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT).

    Science.gov (United States)

    Barandun, Luzi J; Ehrmann, Frederik R; Zimmerli, Daniel; Immekus, Florian; Giroud, Maude; Grünenfelder, Claudio; Schweizer, W Bernd; Bernet, Bruno; Betz, Michael; Heine, Andreas; Klebe, Gerhard; Diederich, François

    2015-01-02

    The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. A Probe into Similarities between Gulian and GAO Jia-lin%于连与高加林相似性探究

    Institute of Scientific and Technical Information of China (English)

    曾丽

    2015-01-01

    The two novels,Stendhal’The Red and the Black and LU Yao’s Life ,are the two mirrors of their own time.Though there exist some differences in their backgrounds,living places and cultures between the protagonists of the two novels Gulian and GAO Jia-lin,they were in the transition of old and new times,they have shown great similarities between their struggling courses and tragic fates.%司汤达《红与黑》和路遥《人生》,是他们各自所处时代社会的一面镜子。两部作品中的主人公于连和高加林虽然存在着出身、生存地域、文化背景的不同,但他们都处于新旧交替时代,其奋斗历程、悲剧命运有许多相似之处。

  11. Comparing the Patriotic Ideas of Lin Zexu and Ye Mingchen%林则徐与叶名琛的爱国思想比较

    Institute of Scientific and Technical Information of China (English)

    李松

    2012-01-01

    In the First Opium War,Lin Zexu,an Imperial Commissioner,destroyed opium in Humen against foreign oppression and thus was honored as the national hero.During the Second Opium War,Ye Mingchen,another Imperial Commissioner,was defeated and captured.Comparing what they did,people had different comments upon them.However,comparing what they did before and after the two Opium Wars,it is claimed in this paper that as government high rank officials both of them were patriotic and Ye Mingchen was misjudged.%在第一次鸦片战争中,林则徐作为钦差大臣,虎门销烟,反抗侵略,被称为民族英雄。在第二次鸦片战争中,钦差大臣叶名琛因亚罗号事件,城破被俘,为世人所唾弃。两人的后世评价可谓大相径庭,有些偏错。文章通过对叶名琛和林则徐在两次鸦片战争前后的表现进行比较,认为林、叶二人作为封疆大吏都具有典型的爱国思想,后人对其不同评价有失公正。